Micronuclei DNA From Peripheral Red Blood Cells and Uses Thereof

ABSTRACT

Provided are peripheral red blood cell micronuclei DNA, a method for extracting the same, and the use of the micronuclei DNA in cancer screening, diagnosis, typing and/or staging.

TECHNICAL FIELD

The present disclosure relates to the fields of biology, medicine andbioinformatics. Particularly, the present disclosure relates toperipheral red blood cell micronuclei DNA and its application in cancerdetection.

BACKGROUND

Cancer is one of the main diseases threatening human health and life. Itis reported that, in 2018, there were 18.1 million new cancer cases and9.6 million cancer deaths worldwide. Nearly half of new cancer cases andmore than half of cancer deaths occurred in Asia (Global CancerStatistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwidefor 36 Cancers in 185 Countries. Bray Freddie et al., CA: A CancerJournal for Clinicians. 2018). Despite decades of continuousexploration, progress has been made in the diagnosis and treatment ofcancer, but there is still a huge demand for cancer detection,especially the screening, diagnosis, classification and staging ofcancer.

Blood continuously circulates in the body, and the total blood of normaladults accounts for about 8% of the body weight of men and about 7.5% ofthe body weight of women. Peripheral blood samples are easy to collect,store and transport and have high stability (Dagur, P. K. and J. J.McCoy, Collection, Storage, and Preparation of Human Blood Cells. CurrProtoc Cytom, 2015. 73: p. 5.1.1-16).

Micronuclei is usually considered as a small nuclear structure formedwhen chromosomes or chromosome fragments are not incorporated into oneof the daughter nuclei during cell division, which is usually a sign ofgenotoxicity events and chromosome instability. Generally, it is a smallnuclear structure formed outside the main nucleus which is independentof the main nucleus, due to the incorrect repair or unrepaired DNAbreakage, or lagging asymmetric chromosome or chromatid fragment causedby chromosome non-separation (Liu, S., et al., Nuclear envelope assemblydefects link mitotic errors to chromothripsis. Nature, 2018. 561(7724):p. 551-555).

Up to now, there is no report on the micronuclei DNA isolated orpurified from peripheral red blood cells, and there is no report on theuse of peripheral red blood cell micronuclei DNA for cancer detection.

SUMMARY

Generally, the present disclosure relates to micronuclei DNA isolated orpurified from peripheral red blood cells, its extraction method, and itsapplication in screening, diagnosis, typing and/or staging of diseases.

The first aspect of the present disclosure relates to micronuclei DNAisolated or purified from peripheral red blood cells.

In some embodiments, the micronuclei DNA isolated or purified fromperipheral red blood cells does not contain or substantially does notcontain nucleated cell genomic DNA.

In some embodiments, the peripheral blood is human peripheral blood. Ina specific embodiment, the peripheral blood is fresh human peripheralblood.

In some embodiments, the micronuclei DNA is used for cancer detection,such as early screening, diagnosis, typing and/or staging of cancer. Insome specific embodiments, the micronuclei DNA is used for diagnosis ofpan-cancer patients, including but not limited to patients sufferingfrom colorectal cancer (also referred to as “CRC” hereinafter),hepatocellular cancer (also referred to as “HCC” hereinafter) or lungcancer (also referred to as “LC” hereinafter).

In some embodiments, the micronuclei DNA is used for early screening,diagnosis, typing and/or staging of cervical cancer.

In some embodiments, the micronuclei DNA is used for early screening,diagnosis, typing and/or staging of cervical cancer, and the micronucleiDNA comprises a gene classifier shown in Table 2, 4 or 6.

In other embodiments, the micronuclei DNA is used for early screening,diagnosis, typing and/or staging of colorectal cancer.

In a further embodiment, the micronuclei DNA is used for earlyscreening, diagnosis, typing and/or staging of colorectal cancer, andthe micronuclei DNA comprises a gene classifier shown in Table 8 or 10.

In some further embodiments, the micronuclei DNA is used for earlyscreening, diagnosis, typing and/or staging of hepatocellular cancer.

In some even further embodiments, the micronuclei DNA is used for earlyscreening, diagnosis, typing and/or staging of lung cancer.

In some even further embodiments, the micronuclei DNA is used fordiscriminating power between each of the two cancer patient groups: CRCvs. HCC, LC vs. HCC, LC vs. CRC.

In some even further embodiments, the micronuclei DNA is used for themulticlass discrimination of different types of cancers. In a specificembodiment, the micronuclei DNA is used for the multiclassdiscrimination of HD (“health donors”), HCC, LC and CRC.

The second aspect of the present disclosure relates to a method forisolating or purifying micronuclei DNA from peripheral red blood cells,which comprises the following steps:

a) providing peripheral blood samples;

b) isolating mononuclear cells and red blood cells from peripheral bloodsamples;

c) collecting red blood cells;

d) treating collected red blood cells with a red blood cell lysisbuffer; and

e) extracting micronuclei DNA from the lysed red blood cells.

In a specific embodiment, the collected red blood cells are subjected totwo or more sequential filtrations, e.g., filtrations by cell strainers,e.g., filtrations by 10 μm cell strainers.

In some embodiments, the red blood cell lysis buffer specifically lysesred blood cells by changing the osmotic pressure of cell suspension, butdoes not lyse nucleated cells.

In some embodiments, the red blood cell lysis buffer comprises NH₄Cl,NaHCO₃, EDTA or a combination thereof.

In some embodiments, micronuclei DNA is extracted from the lysed redblood cells by a DNA extraction reagent. In certain embodiments, the DNAextraction reagent comprises a protease, such as protease K. In certainspecific embodiments, the DNA extraction reagent comprises protease Kand EDTA.

In some embodiments, before step b), a step of diluting the peripheralblood sample is further included, for example, diluting with phosphatebuffer solution in equal volume.

In some embodiments, in step b), the peripheral blood sample issubjected to density gradient centrifugation, such as Ficoll densitygradient centrifugation, to obtain a mononuclear cell layer and a redblood cell layer.

A third aspect of the present disclosure relates to a method forconstructing a gene classifier for cancer detection through peripheralred blood cell micronuclei DNA, which comprises:

a) providing more than one class, wherein each class represents a groupof subjects with common characteristics;

b) isolating or purifying peripheral red blood cell micronuclei DNA fromperipheral red blood cells of each subject of each class;

c) sequencing the whole genome of the peripheral red blood cellmicronuclei DNA to obtain fragment sequence information of themicronuclei DNA;

d) comparing the fragment sequence information of micronuclei DNA fromperipheral red blood cells in different classes of subjects;

e) training the characteristic DNA fragment set for specific cancersaccording to the differences in the distribution of fragment thesequence information of micronuclei DNA in peripheral red blood cells ofdifferent classes of subjects, thus obtaining a gene classifier forspecific cancer detection.

In certain embodiments, the different classes are cancer subjects andnon-cancer subjects for the same cancer.

In certain embodiments, the different classes are subjects withdifferent types of the same cancer.

In certain embodiments, the different classes are subjects at differentstages of the same cancer type.

The fourth aspect of the present disclosure relates to a gene classifierfor cancer detection, which is constructed by peripheral red blood cellmicronuclei DNA.

In certain embodiments, the gene classifier comprises the genes shown inTable 2, 4, 6, 8 or 10.

A fifth aspect of the present disclosure relates to a method of cancerdetection for a test subject, comprising:

a) extracting micronuclei DNA in peripheral red blood cells of the testsubject, wherein the extract does not contain or substantially does notcontain nucleated cell genomic DNA;

b) sequencing the micronuclei DNA and sample-matched genomic DNA bywhole genome sequencing to obtain signature of the micronuclei DNA fromred blood cells in specific genomic elements or different bin size forthe test subject;

c) comparing the sample-matched genomic DNA and micronuclei DNA in redblood cells or micronuclei DNA from different types of samples in stepb) with the whole genome analysis, so as to classify the micronuclei DNAfrom genomic DNA and evaluate the difference of micronuclei DNAsignature from types of samples;

d) comparing the signature information of the micronuclei DNA fromdifferent classes of cancer patients or healthy donors obtained in stepb) with the gene classifier or other deep neural network classifier forcancer detection of the present disclosure, so as to classify the testsubjects into one or more of the classes.

A sixth aspect of the present disclosure relates to a system for cancerdetection of a test subject, which comprises a comparison means forcomparing peripheral red blood cell micronuclei DNA from the testsubject with the gene classifier of the present disclosure.

A seventh aspect of the present disclosure relates to the use of anagent for analyzing micronuclei DNA of peripheral red blood cells in thepreparation of a detection device or a detection kit for cancerscreening, diagnosing, typing and/or staging.

In some specific embodiments, the screening or diagnosis is earlyscreening or diagnosis.

The eighth aspect of the present disclosure relates to peripheral redblood cell micronuclei DNA for use in cancer detection.

The ninth aspect of the present disclosure relates to a method forisolating peripheral red blood cells.

The tenth aspect of the present disclosure relates to the use ofperipheral red blood cells in cancer detection.

The above content is summary in general, so it includes simplification,generalization and omission of details when necessary. Therefore, thoseskilled in the art will recognize that this general summary is merelyillustrative and is not intended to be limiting in any way. Otheraspects, features and advantages of the methods, compositions and/ordevices and/or other subjects described herein will become apparentunder the teachings herein. A summary is provided to simplify theintroduction of some selected concepts, which will be further describedin the following detailed description. This summary is not intended toidentify key features or essential features of the claimed subjectmatter, nor is it intended to be used as an auxiliary means to determinethe scope of the claimed subject matter. In addition, the contents ofall references, patents and published patent applications citedthroughout this application are incorporated herein by reference intheir entirety.

TECHNICAL EFFECTS OF THE INVENTION

The inventors extracted micronuclei DNA from peripheral red blood cellsfor the first time and performed high-throughput sequencing on theextracted micronuclei DNA. Through bioinformatics analysis, erythrocytemicronuclei DNA has been successfully used in cancer screening,diagnosis, risk ranking, typing and staging, which has important guidingsignificance for cancer prevention, treatment and prognosis.

The invention has achieved superior technical effects in at least thefollowing aspects.

Abundancy in Sample Sources

According to the invention, peripheral blood is used as a sample source,and the source is abundant, stable, and easy to obtain, collect, storeand transport.

Effectiveness in the Isolation of Micronuclei DNA from Red Blood Cells

By the method disclosed in the present disclosure, micronuclei DNA inred blood cells can be effectively isolated from human peripheral blood.It has not been reported in the art that micronuclei DNA in red bloodcells can be effectively isolated from human peripheral blood.

Simple and Fast Operation

According to the present disclosure, only a small amount (for example,only 1 ml) of peripheral blood needs to be collected from the subject,which may relieve the psychological pressure of the subject.Particularly, for the detection of cervical cancer, there is no need tocollect cervical exfoliated cells of the subjects, which is easy tooperate and can effectively reduce the psychological pressure of thesubjects.

In addition, by high-throughput sequencing, micronuclei DNA can bequickly sequenced to obtain genetic information.

High Sensitivity and Specificity of Cancer Detection

Using micronuclei DNA obtained from peripheral red blood cells, cancercan be detected with extremely high sensitivity and specificity by themethod of the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more apparent to those skilled in the artthrough the specific embodiments and examples described in the presentdisclosure, combined with the following drawings.

FIG. 1 shows a schematic diagram of isolating peripheral blood cells byFicoll density gradient centrifugation.

FIG. 2 shows that mononuclear cells and red blood cells were collectedafter Ficoll density gradient centrifugation.

FIG. 3 shows the flow chart of sample processing and high-throughputsequencing of peripheral blood mononuclear cell genomic DNA anderythrocyte micronuclei DNA.

FIG. 4 shows the bioinformatics analysis algorithm logic.

FIG. 5 shows hierarchical clustering of healthy individuals and cervicalcancer patients.

FIG. 6 shows hierarchical clustering of patients with different types ofcervical cancer (squamous cell carcinoma and adenocarcinoma).

FIG. 7 shows hierarchical clustering of cervical cancer patients atdifferent stages.

FIG. 8 shows the risk ranking of subjects and screening of cervicalcancer patients by the gene classifier of the present disclosure.

FIG. 9 shows the risk ranking of subjects by the gene classifier of thepresent disclosure, and patients with cervical squamous cell carcinomafrom patients with cervical adenocarcinoma were distinguished.

FIG. 10 shows hierarchical clustering of healthy individuals andpatients with colorectal cancer.

FIG. 11 shows hierarchical clustering of patients with different typesof colorectal cancer (colon cancer and rectal cancer).

FIG. 12 shows the risk ranking of subjects by the gene classifier of thepresent disclosure to screen colorectal cancer patients.

FIG. 13 shows the risk ranking of subjects by the gene classifier of thepresent disclosure to differentiate colon cancer patients from rectalcancer patients.

FIG. 14 shows the multiclass discrimination of HD, HCC, LC and CRCsamples in a training cohort (left), validation cohort (middle) and testcohort (right).

FIG. 15 (FIG. 15A-D) shows the characterization the profile of the redblood cell micronuclei DNA (i.e., a rbcDNA signature) in healthy donorsand cancer patients.

DETAILED DESCRIPTION

While the present invention can be embodied in many different manners,specific illustrative embodiments thereof which demonstrate theprinciples of the invention are disclosed herein. It should beemphasized that the present invention is not limited to the specificembodiments illustrated. In addition, any chapter titles used herein arefor organizational purposes only and should not be interpreted aslimiting the described subject matter.

Unless otherwise defined herein, scientific and technical terms used inconnection with the present invention will have the meanings commonlyunderstood by those of ordinary skill in the art. In addition, unlessthe context requires otherwise, the singular term shall include theplural, and the plural term shall include the singular. Morespecifically, as used in this specification and the appended claims,unless the context clearly indicates otherwise, the singular forms “a,”“an” and “the” include plural referents. Therefore, for example,reference to “a protein” may include a variety of proteins; andreference to “a cell” includes a mixture of cells, etc. In thisapplication, unless otherwise stated, the use of the expression “or”refers to “and/or.” In addition, the use of the term “comprising” andother forms such as “comprise” and “comprises” is not limiting.Furthermore, the ranges provided in the description and the appendedclaims include all values between endpoints and breakpoints.

Generally, the terms related to cell and tissue culture, molecularbiology, immunology, microbiology, genetics, and protein as well asnucleic acid chemistry and hybridization described herein, and theirtechniques are well-known and commonly used in the art. Unless otherwisestated, the methods and techniques of the present invention aregenerally carried out according to conventional methods known in theart, as described in various general and more specific references citedand discussed throughout this specification. See, for example, Abbas etal., Cellular and Molecular Immunology, 6th ed., W. B. Saunders Company(2010); Sambrook J. & Russell D. Molecular Cloning: A Laboratory Manual,3rd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.(2000); Ausubel et al., Short Protocols in Molecular Biology: ACompendium of Methods from Current Protocols in Molecular Biology,Wiley, John & Sons, Inc. (2002); Harlow and Lane Using Antibodies: ALaboratory Manual, Cold Spring Harbor Laboratory Press, Cold SpringHarbor, N.Y. (1998); and Coligan et al., Short Protocols in ProteinScience, Wiley, John & Sons, Inc. (2003). Terms related to analyticalchemistry, synthetic organic chemistry and drugs and pharmaceuticalchemistry described herein, as well as laboratory procedures andtechniques, are well-known and commonly used terms in the field. Inaddition, any chapter titles used herein are for organizational purposesonly and are not to be interpreted as limiting the described subjectmatter.

Definition

In order to better understand the present invention, definitions andinterpretations of related terms are provided as follows.

In the context of the present disclosure, the term “DNA” refers todeoxyribonucleic acid.

In the context of the present disclosure, the term “micronuclei” isintended to refer to a small nuclear structure containing DNA in aspecific cell other than the nucleus. There is no nucleus in peripheralred blood cells, so there is only micronuclei structure.

In the context of the present disclosure, the term “cervical cells”include cells located at any part of the cervix and cells detached fromany part of the cervix that can be diseased. In one embodiment, cervicalcells are cells isolated from tissues exfoliated from that inner wall ofthe cervix in a natural or artificial way, also called “cervicalexfoliated cells.”

In the context of the present disclosure, a “subject” refers to asubject to be tested. In certain embodiments, the “subject” is a humansubject.

In the context of the present disclosure, a “patient” refers to asubject suffering from a certain disease, such as cervical cancer.

In the context of the present disclosure, “cancer” is a general term formalignant tumors. “Tumor” refers to the abnormal proliferation of cellsin local tissues under the influence of various tumorigenic factors.

In the context of the present disclosure, a “cancer subject” or a“cancer patient” are used interchangeably, referring to a subjectsuffering from a certain cancer, such as cervical cancer or colorectalcancer.

In the context of the present disclosure, a “non-cancer subject” refersto a subject who does not suffer a certain cancer. For example,“non-cervical cancer subject” refers to a subject without cervicalcancer. In the specific embodiments and examples of the presentdisclosure, a “non-cancer subject” is also referred to as a “healthyindividual,” and likewise, it refers to that the individual or subjectdoes not have such cancer.

In the context of the present disclosure, the term “cancer detection”refers to detecting the condition of a subject suffering from cancer.“Detecting” includes but is not limited to screening, diagnosis, typingand staging. “Screening” refers to preliminarily detecting whether thereis cancer or the risk of cancer. “Diagnosis” or “medical diagnosis”refers to assessing the patient's condition from a medical point ofview. “Typing” refers to further dividing the same kind of cancer intospecific subtypes. For example, cervical cancer can be classified intocervical squamous cell carcinoma and cervical adenocarcinoma. “Staging”refers to predicting, assessing or dividing the stage of a cancer. Forexample, cervical cancer (squamous cell carcinoma) can be divided intothree stages: low differentiation, low-medium differentiation, mediumdifferentiation and high differentiation.

In the context of the present disclosure, the term “nucleated cell”refers to a cell in which a nucleus exists. For peripheral blood, theterm “nucleated cell” is the general term for a granulocyte, a monocyteand a lymphocyte.

In the context of the present disclosure, the term “genome” refers tothe sum of all genetic information in a cell, especially a complete setof haploid genetic material in a cell.

In the context of the present disclosure, the term “nucleated cellgenomic DNA,” “nucleated cell nucleus genome,” or “nucleated cellnucleus genomic DNA” are used interchangeably, meaning all geneticinformation contained in nuclear chromosomes.

In the context of the present disclosure, the term “gene classifier” or“classifier” can be used interchangeably, referring to a group of DNAfragments or a group of genes in genomic DNA or micronuclei DNA that arespecific for a specific disease.

In the context of the present disclosure, the term “DNA fragmentlibrary” or “DNA library” can be used interchangeably, which refers todouble-stranded DNA obtained by completing the ends of a sample DNAfragment, adding a phosphate group at the 5′ end, adding an adeninenucleotide (A) at the 3′ end, and connecting an adapter and a samplebarcode at both ends.

In the context of the present disclosure, the term “micronuclei DNA fromred blood cells” and “erythrocyte micronuclei DNA” are usedinterchangeably, and is intends to refer micronuclei DNA isolated fromred blood cells. In a specific embodiment, the red blood cells areperipheral red blood cells. Accordingly, in the context of the presentdisclosure, “peripheral red blood cells micronuclei DNA, “peripheralerythrocyte micronuclei DNA”, and “micronuclei DNA from peripheral redblood cells” are used interchangeably. In a specific embodiment,micronuclei DNA is isolated or purified from peripheral red blood cells.

In the context of the present disclosure, the term “high-throughputsequencing” (also known as Next-Generation Sequencing (NGS)) refers toDNA sequencing technology that simultaneously sequences thousands (evenmillions) of DNA templates in a single chemical reaction.

In the context of the present disclosure, the term “reads” refers to thesequence of a sample DNA fragment in a DNA fragment library measured byhigh-throughput sequencing, with the sequence linked in the librarypreparation stage removed.

In the context of the present disclosure, the term “coverage depth”refers to an effective nucleic acid sequencing fragment for baserecognition in a specific region, also known as the number of reads.

In the context of the present disclosure, the term “sequence alignment”refers to the alignment of reads to a reference genome (e.g., a humanreference genome) by the principle of sequence identity.

In the context of the present disclosure, the term “reference genome” isthe whole genome sequence of an organism of the same species as thesample DNA, which can be obtained from a public database. In oneembodiment, the reference genome is a human reference genome. The publicdatabase is not particularly limited. In some embodiments, the publicdatabase is GenBank database of NCBI.

In the context of the present disclosure, the term “sensitivity” refersto the percentage of samples with positive tests in the total number ofpatients. In medical diagnosis, sensitivity can be expressed by thefollowing formula, reflecting the ratio of correctly diagnosingpatients:

Sensitivity=true positive number/(true positive number+false negativenumber) ×100%.

In short, if “true positive,” “false positive,” “true negative” and“false negative” are represented by “a”, “b”, “c” and “d”, respectively,the relationship among sensitivity, specificity, missed diagnosis rate,misdiagnosis rate and accuracy can be shown as follows.

Pathological diagnosis (gold standard) Screening method DiseasedNon-diseased Sum Positive (+) True positive (a) False positive (b) a + bNegative (−) False negative (c) True negative (d) c + d Sum a + c b + da + b + c + d

Among the cases with positive screening results by this method, “truepositive (a)” refers to the number of cases diagnosed as diseased bypathology, and the result of a method is also positive; “false positive(b)” refers to the number of cases diagnosed as non-diseased bypathology, and the result of a method is positive; “false negative (c)”refers to the number of cases diagnosed as diseased by pathology and theresult of a method is negative; and “true negative (d)” refers to thenumber of cases diagnosed as non-diseased by pathology and the result ofa method is negative.

Sensitivity(sen)=a/(a+c);

Specificity(sep)=d/(b+d);

Missed diagnosis rate=c/(a+c);

Misdiagnosis rate=b/(b+d);

Accuracy=(a+d)/(a+b+c+d)

As known by those skilled in the art, the higher the value ofsensitivity and specificity, the better; and the lower the misseddiagnosis rate and misdiagnosis rate, the better.

In the context of the present disclosure, the term “specificity” refersto the percentage of samples with negative tests in healthy people inthe total number of healthy people. In medical diagnosis, “specificity”can be expressed by the following formula, which reflects the ratio ofcorrect diagnosis of non-patients:

Specificity=true negative number/(true negative number+false positivenumber)×100%.

In the context of the present disclosure, the term “missed diagnosisrate,” also known as false negative rate, refers to the percentage ofpatients who are actually diseased when screening or diagnosing adisease in a population, but are determined as non-patients according tothe diagnostic criteria. In medical diagnosis, the missed diagnosis ratecan be expressed by the following formula:

Missed diagnosis rate=false negative number/(true positive number+falsenegative number)×100%.

In the context of the present disclosure, the term “misdiagnosis rate,”also known as false positive rate, refers to the percentage of subjectswho do not actually suffer from a disease when screening or diagnosing adisease in a population, but are determined as patients with such adisease according to the diagnostic criteria. In medical diagnosis, themisdiagnosis rate can be expressed by the following formula:

Misdiagnosis rate=false positive number/(true negative number+falsepositive number)×100%.

In the context of the present disclosure, the expression “about” refersto that the deviation does not exceed plus or minus 10% of a specifiedvalue or range.

Peripheral Blood

In the present disclosure, “peripheral blood” refers to blood releasedinto the circulatory system by hematopoietic organs and participating inthe circulation. “Peripheral blood” is different from immature bloodcells in hematopoietic organs such as bone marrow. In the presentdisclosure, peripheral blood can be collected by reference to knownmethods in the art such as venous blood collection, fingertip bloodcollection or earlobe blood collection.

Generally, peripheral blood consists of plasma and blood cells, whereinthe blood cells further include white blood cells (also called“leukocytes”), red blood cells and platelets. By volume, red blood cellsaccount for about 45%, plasma accounts for about 54.3%, and white bloodcells account for about 0.7% of the total peripheral blood. Leukocytesare nucleated cells, which are the general term of granulocytes,monocytes and lymphocytes. Normal red blood cells have no nucleus, nogenomic DNA, and are nuclear-free cells.

In the context of the present disclosure, a “peripheral bloodmononuclear cell” (PBMC) refers to a cell with a single nucleus inperipheral blood, including monocytes and lymphocytes.

Separation of Peripheral Blood Cells

The separation methods of peripheral blood cells include naturalsedimentation, differential sedimentation, sodium chloride separation,density gradient centrifugation and so on.

Different components of peripheral blood can be separated by using thedensity difference between different components of peripheral blood. Forexample, different components of peripheral blood can be separated byFicoll density gradient centrifugation or Percoll method.

In a specific embodiment of the present disclosure, peripheral blood isseparated by Ficoll density gradient centrifugation. Specifically, it iscarried out in the following ways:

1. Peripheral Blood Collection and Sample Preparation

Peripheral blood is obtained from a subject and diluted appropriately.For example, it can be diluted by adding phosphate buffer solution(PBS). In certain embodiments, about 1-5 ml of fresh peripheral blood isobtained from a subject and diluted by adding an equal volume of PBS toobtain a diluted blood sample. In a specific embodiment, 1 ml of freshperipheral blood is obtained from a subject, and 1×PBS is added forequal volume dilution to obtain diluted peripheral blood samples.

2. Density Gradient Centrifugation of Peripheral Blood Samples

Initially, an appropriate amount of Ficoll density gradient centrifugeis added into the density gradient centrifuge tube, and then the dilutedperipheral blood sample as described above is add thereto. In certainembodiments, an appropriate amount of Ficoll density gradient centrifugeis added to the density gradient centrifuge tube in a ratio of thevolume of peripheral blood collected from the subject to the volume ofFicoll density gradient centrifuge of about 1:3 to 1:10. For example, ina specific embodiment, 1 ml of fresh peripheral blood is obtained from asubject, and 5 ml of Ficoll density gradient centrifuge (Stemcell,Lymphoprep™ 07801) is added to the density gradient centrifuge tube.

Then, the diluted peripheral blood sample was slowly added onto theFicoll density gradient centrifuge in the Ficoll density gradientcentrifuge tube for density gradient centrifugation. Density gradientcentrifugation can be carried out for about 10-15 minutes at about15-25° C. and at about 1000-1500 g g. In a specific embodiment, thedensity gradient centrifugation is performed by 1200 g centrifugation at18° C. for 15 minutes.

After density gradient centrifugation, it is divided into three layers:the upper layer is plasma, the middle layer is PBMC layer, and thebottom layer is RBC layer.

Collection of PBMC and RBC respectively. For example, the middle andupper layer liquid in the density gradient centrifuge tube is sucked bya suction means (such as a straw), and PBMC is separated and collected.An extraction means (such as a needle tube) is used to extract bottomred blood cells from the bottom of the density gradient centrifuge tube,and RBCs are separated and collected. In a specific embodiment, thebottom red blood cells are extracted from the bottom of the densitygradient centrifuge tube by using a needle tube to a 1.5 ml centrifugetube, with 1×PBS added up to a volume of 1 ml. Centrifugation isconducted at room temperature for 10 min at 300 g, and red blood cellsat the bottom of the tube are collected. The collected RBCs were thensubject to two sequential filtrations by 10 μm cell strainers to removepotential contamination of nucleated cells.

Isolation of Micronuclei DNA from Peripheral Red Blood Cells

According to the inventor's knowledge, there is no report on isolatingmicronuclei DNA from human peripheral red blood cells in the prior art.Unexpectedly, the inventors found that the micronuclei DNA of peripheralred blood cells can be separated simply and efficiently by the method ofthe present disclosure. In certain embodiments, the collected red bloodcells are first lysed and then centrifuged. Thereafter, micronuclei DNAwas extracted from the supernatant after centrifugation. In certainembodiments of the present disclosure, “peripheral red blood cellmicronuclei DNA” includes all DNA present in peripheral red blood cells.In a specific embodiment of the present disclosure, the isolated“peripheral red blood cell Micronuclei DNA” does not contain nucleatedcell genomic DNA. In another specific embodiment of the presentdisclosure, isolated “peripheral red blood cell micronuclei DNA”substantially does not contain nucleated cell genomic DNA.

The inventors also unexpectedly found that micronuclei DNA isolated fromperipheral red blood cells can be used to detect various cancers.

Lysis of Red Blood Cells

In some embodiments, the collected red blood cells are lysed by adding ared blood cell lysis buffer. Erythrocyte lysis buffer can lyseerythrocytes while hardly damaging nucleated cells (such as PBMC). Itcan lyse erythrocytes effectively by slightly changing the osmoticpressure of cell suspension without affecting all nucleated cells. Thered blood cell lysis buffer commonly used in the art contains NH₄Cl,NaHCO₃, EDTA or other combinations, for example, NH₄Cl, NaHCO₃ and EDTA.For example, every 1000 ml of red blood cell lysis buffer contains 8.3 gNH₄Cl, 1.0 g NaHCO₃, 1.8 ml of 5% EDTA and ultra-pure water.

The red blood cell lysis buffer can be, for example, a red blood celllysis buffer (Biosharp, Cat No./ID: BL503B), a red blood cell lysisbuffer (Solarbio, Cat No./ID: R1010) or a BD FACS Lysing Solution redblood cell lysis buffer (BD, Cat No./1 D: 349202). In a specificembodiment, 10 ml of red blood cell lysis buffer (Biosharp, Cat No./ID:BL503B) is added to the collected red blood cells, and the collected redblood cells are lysed for 20 minutes at room temperature in the dark.

Centrifugation

Thereafter, supernatant and precipitate (cell debris) are separated bycentrifugation. In a specific embodiment, centrifugation is performed at3000 g at room temperature for 10 minutes, and then the supernatant istaken.

Isolation of Micronuclei DNA

Then, micronuclei DNA is extracted from the supernatant. In certainembodiments, the DNA contained in the supernatant is pretreated byadding EDTA and protease K. EDTA is added in the digestion process withprotease K to inhibit the influence of Mg²⁺-dependent nuclease. In aspecific embodiment, the supernatant is incubated with 10 mm EDTA(Solarbio Cat No./ID: E1170), 200 ug/ul protease K (ProteinaseK, Ambion,Cat No./ID: AM2548) at 56° C. for 8 hours.

After incubation, commercial kits or reagents are used to extractmicronuclei DNA. Examples of commercial kits include but are not limitedto QIAamp DNA Blood Mini Kit, DNAzol reagent, PureLink™ Pro 96 GenomicDNA Purification Kit (Thermo, Cat No./ID: K182104A), blood genomic DNAextraction system (0.1-20 ml) (TIANGEND, Cat No./ID: P349), HiPure BloodDNA Midi Kit III(Magen, Cat No./ID: D3114). In a specific embodiment,erythrocyte micronuclei DNA is extracted using QIAamp DNA Blood Mini Kit(Qiagen, Cat No./ID: 51106).

Extraction of Genomic DNA from Peripheral Blood Mononuclear Cells

The genomic DNA of peripheral blood mononuclear cells can be extractedby commercial kits. In a specific embodiment, for peripheral bloodmononuclear cell samples obtained after density gradient centrifugation,genomic DNA is extracted using QIAamp DNA Blood Mini Kit (Qiagen, CatNo./ID: 51106).

Whole Genome Amplification

Whole-genome amplification (WGA) is non-selective amplification of thewhole genome sequence. Its main purpose is to maximize the amount of DNAon the basis of faithfully reflecting the whole genome, and to amplifythe whole genome DNA of micro tissues and single cells without sequencebias.

Whole-genome amplification methods are mainly divided into the followingtypes: first, amplification technology based on thermal cycles and PCR;second, amplification technology based on isothermal reaction and notbased on PCR; and the third is MALBAC (Multiple Annealing andLooping-based Amplification Cycles). The WGA technology based on PCRincludes degenerate oligonucleotide primer PCR (DOP-PCR), linker-adapterPCR (LA-PCR), interspersed repeat sequence PCR (IRS-PCR), tagged randomprimer PCR (T-PCR), primer extension preamplification PCR (PEP-PCR),among others. WGA based on isothermal reaction includes multipledisplacement amplification (MDA), primase-based whole genomeamplification (pWGA) and so on.

The methods of amplifying the whole genome DNA of a single cell mainlyinclude MDA, MALBAC and DOP-PCR. These amplification methods can amplifypg-level or fg-level DNA in cells to μg-level which can satisfysequencing.

Multiple Displacement Amplification (MDA)

Multiple displacement amplification (MDA) was first proposed by Dr.Lizardi of Yale University in 1998. This method is a constanttemperature amplification method based on the principle of stranddisplacement amplification. Phage 129 DNA polymerase was used inmultiple displacement amplification. PhageΦ29 DNA polymerase has astrong binding ability to DNA template, which can continuously amplify100 Kb DNA template without dissociation from the template. At the sametime, the enzyme has 3′-5′ exonuclease activity and low amplificationerror rate.

Multiple displacement amplification has the following advantages:

-   -   samples need not be purified;    -   stable yield;    -   uniform amplification of the genome;    -   amplification with high fidelity;    -   simple operation, independent of PCR reaction.

Commercial kits for MDA include REPLI-g series kits (Qiagen Inc),GenomiPhi series kits (GE Healthcare Inc), among others.

MALBAC (Multiple Annealing and Looping-Based Amplification Cycles)

MALBAC is different from non-linear or exponential amplification, butuses special primers to make the ends of amplicon complementary to eachother. In this technique, the unique DNA polymerase with stranddisplacement activity is used for quasi-linear whole genomepre-amplification, and then exponential amplification is performed byPCR technology, which provides sufficient experimental materials fordownstream analysis. In 2012, Science magazine published two articlesrelated to this technology (C. Zong et al., Science 2012: 1622-1626; S.Lu et al., Science: 1627-1630).

MALBAC has the following advantages:

-   -   high amplification success rate;    -   good uniformity;    -   high coverage.

Commercial kits for MALBAC include MALBAC® single cell amplification kitfrom YiKon.

Degenerate Oligonucleotide Primer PCR(DOP-PCR)

The difference between DOP-PCR and conventional PCR is that it uses asingle semi-degenerate primer and low renaturation temperature, has nospecies specificity, has no relation with the complexity of DNA, and canuniformly amplify the whole genome.

Commercial kits for DOP-PCR include PicoPlex series kits (RubiconGenomics Inc), GenomePlex series kits (Sigma Aldrich Inc), SurePlexseries kits (BlueGnome, which has been acquired by Illumina) and so on.

In the present disclosure, PBMC genomic DNA and RBC micronuclei DNA canbe amplified by the whole genome amplification methods known in the art.In a specific embodiment, PBMC genomic DNA and RBC micronuclei DNA areamplified by MDA. Specifically, for PBMC genomic DNA and RBC micronucleiDNA extracted by QIAamp DNA Blood Mini Kit (Qiagen, Cat No./ID: 51106),MDA was performed by using REPLI-g Single Cell Kit (Qiagen, Cat No./ID:150345), respectively. And the amplified DNA sample is obtained.

The REPLI-g Single Cell Kit adopts multiple displacement amplification(MDA) technology, which can uniformly amplify single cell or purifiedgenomic DNA, and can cover all loci of genome. All buffers and reagentsare produced through a strictly controlled process to avoid DNAcontamination and ensure reliable results for each experiment.

Library Construction

A library is constructed by fragmenting the genomic DNA into short DNAmolecules, then connecting the fragmented genomic DNA to universaladaptors, and then generating millions or even more single-moleculemulti-copy PCR clone arrays.

In the present disclosure, any conventional method in the field can beused to fragment the amplified DNA and construct a DNA fragment library.For example, a commercially available kit can be used to fragmentgenomic DNA and construct a library of DNA fragments.

In certain embodiments, the process of fragmenting genomic DNA andconstructing a DNA fragment library by using a kit may include:

(i) performing fragmentation on genomic DNA;(ii) carrying out terminal modification on the obtained DNA fragments:

-   -   End Repair,    -   adding a phosphate group to the 5′ end of the DNA fragment        repaired as above, and    -   adding an adenine nucleotide (A) to the 3′ end of the DNA        fragment repaired as above (A-tailing);        (iii) ligating an adapter and a sample barcode at the ends of        the DNA fragment modified as above;        (iv) Fragment Selection: agarose gel electrophoresis is        performed on the ligation products as above, and the DNA        fragments (i.e., DNA fragment library) correctly ligated with        the adaptor and the sample barcode were recovered by using any        commercially available kit.        (v) Library Amplification: the DNA fragments with the adaptor        and the sample barcode correctly ligated as above is amplified        by polymerase chain reaction (PCR).

In a specific embodiment of the present disclosure, after MDA, theamplified DNA samples are subjected to secondary sequencing libraryconstruction using TruePrep DNA Library Prep Kit V2 for Illumina(Vazyme, TD503).

High Throughput Sequencing

In the present disclosure, as long as the high-throughput sequencing ofthe DNA fragment library can be realized, there is no specialrestriction on the sequencing method and apparatus adopted. In certainembodiments, the library of DNA fragments is high-throughput sequencedusing a commercially available sequencer. For example, thehigh-throughput sequencing of DNA fragment library can be performed byusing a sequencer from Illumina, a sequencer from Apply Biosystems(ABI), a sequencer from Roche, a sequencer from Helicos, or a sequencerfrom Complete Genomics.

In a specific embodiment, the genomic DNA of peripheral bloodmononuclear cells and erythrocyte micronuclei DNA are sequenced byNovo-seq platform (NovaSeq 6000, from Novogene, Beijing), with10×sequencing depth and 30 G data volume.

In the specific embodiment of the present disclosure, the originalsequencing files for sequencing the erythrocyte micronuclei DNA and thegenomic DNA of peripheral blood mononuclear cells are stored in FASTQfiles. FASTQ is a standard text-based format to save biologicalsequences (usually nucleic acid sequences) and their sequencing qualityinformation.

Bioinformatics Analysis

After high-throughput sequencing, bioinformatics analysis of theobtained sequencing results generally includes quality control, datacomparison, post-alignment processing, among others.

In certain embodiments of the present disclosure, quality control isperformed on the original sequencing files of erythrocyte micronucleiDNA, and the sequencing data passing the quality control is comparedwith the reference genome, and then post-processing is performed.

In a further embodiment of the present disclosure, quality control isperformed on genomic DNA of peripheral blood mononuclear cells, andsequencing data passing the quality control is compared with a referencegenome.

Quality Control

The sequencing data is quality controlled by data quality controlsoftware. The process of quality control includes adapter removal,filtering of low-quality reads, removal of low-quality 3′ and 5′ ends,removal of reads with more N, inspection of data quality, etc. Commonlyused data software includes FastQC, Fastx_toolkit, Trimmomaic and so on.

As the most classic quality control software, FastQC can make quickstatistics on gene information of high-throughput sequencing data andgive corresponding chart reports. The software can be obtained at thefollowing website:http://www.bioinformatics.babraham.ac.uk/projects/fastqc/.

In addition, Fastx_toolkit software can be obtained at the followingwebsite: http://hannonlab.cshl.edu/fastx_toolkit/; and Trimmomaicsoftware can be obtained through the following web site:http://www.usadellab.org/cms/?page=trimmomatic.

In a specific embodiment of the present disclosure, the originalsequencing files of erythrocyte micronuclei DNA and genomic DNA ofperipheral blood mononuclear cells are subjected to adaptor removal bycutadapter software (Kong, Y., Btrim: a fast, lightweight adapter andquality trimming program for next-generation sequencing technologies.Genomics, 2011. 98(2): p. 152-3), and the quality control is carried outby FastQC software.

Data Comparison

After quality control, the data passed the quality control will becompared to the reference genome by a software. Sequencing datacomparison software commonly used in this field includes BWA, Bowtie,Maq, Novoalign, etc., which can be obtained from the following website:

BMA: http://bio-bwa.sourceforge.net

Bowtie: http://bowtie-bio.sourceforge.net

Maq: http://maq.sourceforge.net

Novoalign: http://www.novocraft.com/products/novoalign/

In certain embodiments of the present disclosure, the sequencing data oferythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells can be compared to reference genomes, such as humangenomes, respectively, through data comparison software in the field. Ina specific embodiment of the present disclosure, the sequencing data oferythrocyte micronuclei DNA and peripheral blood mononuclear cell genomeDNA were compared to human genome (GenBank) by BWA software.

Post-Alignment Processing of Data

Post-alignment processing may include the following situations, such asremoving duplicate reads, Indel local re-alignment, re-proofreading ofbase mass values, and so on. Whether or not to carry out post-alignmentprocessing is determined according to actual needs. The commonly usedpost-alignment processing includes removing duplicate reads. Differentreads aligned onto the same position of the reference genome may beconsidered as duplication due to quality problems, sequencing errors,alignment errors, alleles, among others.

In some embodiments of the present disclosure, post-alignment processingis performed by removing duplicate reads. In a specific embodiment ofthe present disclosure, improper alignment and repeated reads areremoved by Picard software (Weisenfeld, N. I., et al., Directdetermination of diploid genome sequences. Genome Res, 2017. 27(5): p.757-767). Picard software can be obtained from the following website:

http://broadinstitute.github.io/picard/

Data Analysis

After data processing, the sequencing data obtained are analyzed.

Comparison and Counting of Reads

In certain embodiments of the present disclosure, whether there aresignificant differences in the fragmentation degree of DNA fragments inred blood cells of different types of subjects is compared. For example,the reads of sequencing fragments existing in micronuclei DNA of samplescan be counted by software for reads counting (such as HTseq-count,featureCounts, BEDTools, Qualimap, Rsubread, GenomicRanges, etc.).Variance analysis (such as ANOVA test) is applied to judge whether thereis a significant difference therebetween.

In certain specific embodiments of the present disclosure, the reads ofsmall sequencing fragments existing in erythrocytes micronuclei DNA arecounted corresponding to the gene regions of human genome by HTseq-countsoftware (Anders, S., P. T. Pyl and W. Huber, HTSeq-a Python frameworkto work with high-throughput sequencing data. Bioinformatics, 2015.31(2): p. 166-9).

In a specific embodiment of the present disclosure, one class isperipheral red blood cell micronuclei DNA from cervical cancer patientsand the other class is peripheral red blood cell micronuclei DNA fromhealthy individuals.

In another specific embodiment of the present disclosure, one class isperipheral red blood cell micronuclei DNA from patients with cervicaladenocarcinoma and the other class is peripheral red blood cellmicronuclei DNA from cervical squamous cell carcinoma.

In another specific embodiment of the present disclosure, one class isperipheral red blood cell micronuclei DNA from medium-differentiatedpatients in cervical squamous cell carcinoma, and the other class isperipheral red blood cell micronuclei DNA from low-medium differentiatedor low differentiated patients in cervical squamous cell carcinoma.

In a further embodiment of the present disclosure, one class isperipheral red blood cell micronuclei DNA from colorectal cancerpatients and the other class is peripheral red blood cell micronucleiDNA from healthy individuals.

In a further embodiment of the present disclosure, one class isperipheral red blood cell micronuclei DNA from colon cancer patients andthe other class is peripheral red blood cell micronuclei DNA from rectalcancer.

Data Classification and Classifier Construction

Classification is an important method of data mining. Based on theexisting data, a classification function is learned or a classificationmodel is constructed, which also called a classifier. Classifiers canmap data records in the database to a given class, which can be appliedto data prediction. Classification methods include decision tree,selection tree, logistic regression, Naive Bayes and deep neuralnetwork.

In certain embodiments of the present disclosure, genes with significantdifferences are selected as features, and a classifier is constructedfor known classified samples based on support vector machine (SVM) topredict the specific disease classification of unknown samples (Huang,M. W., et al., SVM and SVM Ensembles in Breast Cancer Prediction. PLoSOne, 2017. 12(1): p. e0161501). In some specific embodiments of thepresent disclosure, through the hierarchical clustering-based supportvector machine algorithm, a classifier composed of a group of genescorresponding to DNA fragments is constructed. In a specific embodimentof the present disclosure, two types of samples are randomly clusteredaccording to Pearson correlation to construct a classifier composed of agroup of genes.

In certain embodiments of the present disclosure, specific regions oferythrocyte micronuclei DNA are further selected before constructing theclassifier.

In certain embodiments of the present disclosure, macs2 software is usedto search for the fragments of erythrocyte micronuclei DNA which aremainly enriched in a specific region relative to the genome DNAsequencing reads of peripheral blood mononuclear cells, and to removethe peak areas which are more enriched by peripheral blood mononuclearcells relative to peripheral blood mononuclear cells per se as a whole.Compared with peripheral blood mononuclear cells, genome informationannotation and pathway enrichment (KEGG, gene ontology) were performedon red blood cell-specific fragments (Chen, L., et al., Gene Ontologyand KEGG Pathway Enrichment Analysis of a Drug Target-BasedClassification System. PLoS One, 2015. 10(5): p. e0126492.).

Application of Classifier

On the basis of the classifier constructed in the present disclosure,the present invention can be widely used in biological research, medicalresearch, clinical diagnosis and other fields by isolating peripheralblood micronuclei DNA from subjects in the manner described in thepresent disclosure and performing biological analysis. The invention hasimportant value in scientific research and medical fields.

Application of the Invention

The inventors have successfully isolated erythrocyte micronuclei DNAfrom peripheral blood and applied it to cancer detection for the firsttime, including screening, diagnosis, typing and staging of cancer.

Among cancers, cervical cancer and colorectal cancer account for a largeproportion of new cases and fatal cases.

Cervical Cancer

Cervical cancer is one of the most common gynecological tumors, and itsincidence is increasing year by year. According to the statistics of theWorld Health Organization (WHO), there are an average of 530,000 newcases of cervical cancer every year, and about 250,000 women die fromcervical cancer, among which developing countries account for 80% of theglobal total cases (Schiffman, M., et al., Carcinogenic humanpapillomavirus infection. Nat Rev Dis Primers, 2016. 2: p. 16086). InChina, there are about 140,000 new cases of cervical cancer and about37,000 deaths every year. Therefore, early screening and clinicalstaging of cervical cancer patients are of great significance to thetreatment of cervical cancer.

Pathogenic Factors of Cervical Cancer

Pathogenic factors of cervical cancer include but are not limited to thefollowing aspects:

Virus Infection

HPV infection is the main pathogenic factor of cervical cancer. Thereare many subtypes of HPV, about 40 of which are related to reproductivetract infection. Continuous infection by high-risk HPV subtypes(subtypes 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 69),especially HPV subtypes 16 and 18 can cause cervical cancer.

Sexual Behavior and Number of Deliveries

Other Biological Factors

Chlamydia trachomatis, herpes simplex virus type II, trichomoniasis andother pathogens have synergistic effects in the pathogenesis of cervicalcancer caused by high-risk HPV infection.

Other Behavioral Factors

Smoking as a synergistic factor of HPV infection can increase the riskof cervical cancer. In addition, malnutrition and poor sanitation canalso affect the occurrence of diseases.

Early Screening Method for Cervical Cancer in the Prior Art

At present, the early screening of cervical cancer is mainly carried outby virus detection and cytological detection. Among them, virusdetection is mainly human papillomavirus (HPV) detection, whilecytological detection mainly includes Pap smear and TCT detection.

(1) HPV Detection

HPV can cause squamous epithelial proliferation of human skin mucosa.According to its pathogenicity, it can be divided into low-risk type andhigh-risk type. Low risk infection can cause common warts, genital warts(condyloma acuminatum) and other symptoms. Persistent high-risk humanpapillomavirus (HPV) infection is the main cause of cervical cancer.Molecular epidemiological analysis shows that some types of humanpapillomavirus (HPV) are the main causes of invasive cervical cancer andcervical intraepithelial neoplasia. At present, more than 80 types ofHPV have been found, and about 40 of them can infect reproductive tract[Schiffman, M., et al., Carcinogenic human papillomavirus infection. NatRev Dis Primers, 2016. 2: p. 16086; Munoz, N., et al., Epidemiologicclassification of human papillomavirus types associated with cervicalcancer. N Engl J Med, 2003. 348(6): p. 518-27.]. Among them, high-riskHPV (such as HPV 16 and HPV 18) is often associated with invasivecervical cancer. The detection methods of high-risk HPV mainly includemorphological observation, immunohistochemistry, dot-blot hybridization,in situ blotting hybridization, PCR/RFLP, PCR/Southern and so on.

Screening cervical cancer by HPV virus detection can identify more than95% of precancerous cervical lesions, but it is mainly aimed at patientswith cervical intraepithelial neoplasia (CIN) grade 2 or more, while thespecificity for CIN2 negative patients is relatively low, because mostwomen have spontaneous clearance after transient HPV infection, andhardly progress to C1N3 and cancer (Cook, D. A., et al., Evaluation of avalidated methylation triage signature for human papillomavirus positivewomen in the HPV FOCAL cervical cancer screening trial. Int J Cancer,2018). HPV detection can only determine whether women are infected withcarcinogenic HPV, but cannot determine the risk of individual cancer,and there are still few HPV negative cervical cancer patients.Therefore, there may be false positives in HPV testing. On the basis ofHPV detection, it is usually necessary to combine other clinicaldetection indications for subsequent diagnosis.

(2) Pap Smear

Pap Smear, also known as cervical smear or Pap test, is a traditionaland most commonly used screening method for cervical cancer. In thismethod, the cervical exfoliated cells are collected, stained andmicroscopically observed to test whether there are precancerous cells orcancer cells on the cervix, which has always been regarded as the “goldstandard” for cervical cancer detection (Rodriguez, A. C. and J.Salmeron, Cervical cancer prevention in upper middle-income countries.Prev Med, 2017. 98: p. 36-38).

Combined with pathological observation, Pap smear can clearly identifythe development of cervical cancer, but this method can only detectabout 50% of cervical precancerous lesions. The difference in samplecollection quality, insufficient cell collection, fewer abnormal cells,and the shielding of abnormal cells by blood or inflammatory cells willaffect smear observation, resulting in poor detection sensitivity (Cook,D. A., et al., Evaluation of a validated methylation triage signaturefor human papillomavirus positive women in the HPV FOCAL cervical cancerscreening trial. Int J Cancer, 2018). At the same time, due to thelimitation of sampling, it is difficult to have regular detection andtrace cases.

(3) TCT Detection

TCT test, also named as liquid-based thin-layer cytology test, collectscervical cell samples through a special sampler, but does not directlycarry out smear observation, and instead puts the collector into aculture bottle filled with cell preservation solution for rinsing toobtain enough cell samples (Massad, L. S., et al., 2012 updatedconsensus guidelines for the management of abnormal cervical cancerscreening tests and cancer precursors. Obstet Gynecol, 2013. 121(4): p.829-46). After that, the cell sample bottles were sent for laboratoryinspection, and the cell samples were dispersed and filtered byautomatic cell detector, so as to reduce the interference of blood,mucus and inflammatory tissues and obtain a thin cervical cell layer forfurther microscopic detection and diagnosis.

TCT detection is an optimized detection scheme for pap smear of cervicalcancer developed in recent decades. Compared with the traditional Papsmear of cervical cancer, TCT detection significantly improved thesatisfaction of specimens and the detection rate of abnormal cells ofcervical cancer. The detection rate of cervical cancer cells by TCT was100%, and some precancerous lesions could also be found (Andy, C., L. F.Turner and J. O. Neher, Clinical inquiries. Is the ThinPrep better thanconventional Pap smear at detecting cervical cancer? J Fam Pract, 2004.53(4): p. 313-5). However, the detection rate of TCT for cervicalprecancerous lesions is still low, and the sensitivity for earlyscreening and detection of cervical cancer is low, and there are stillmany atypical squamous cells (ASC-US) and atypical glandular cells (AGC)with unknown meanings.

The above methods still have some limitations. First of all, for theabove-mentioned methods, it is often necessary to use combined screeningmethods in clinical use (Zigras, T., et al., Early Cervical Cancer:Current Dilemmas of Staging and Surgery. Curr Oncol Rep, 2017. 19(8): p.51). Secondly, at present, the samples used for cervical cancerscreening by the above method are cervical exfoliated cells, and thesampling method will inevitably cause damage and psychological burden topatients, and at the same time, there are certain restrictions onsampling requirements, and the quality of samples is difficult tocontrol. In addition, screening for cervical cancer often requiresregular detection. According to FDA standards, for women over 21 yearsold, regular detection should be conducted every 3 years to assess therisks. The large fluctuation of sampling quality stability may lead tothe loss of long-term regression testing. Therefore, a more reliable andstable sample source is needed to provide a more dynamic, accurate andinstructive monitoring method and system for cervical cancer screening.

In the context of the present disclosure, “cervical cancer” includes anytype of cervical cancer.

Classification and Staging of Cervical Cancer

The occurrence and development of cervical cancer has a gradualevolution process, which can last from several years to several decades.It is generally considered that the evolution can be divided intoseveral stages: mild intraepithelial neoplasia (CINI), moderateintraepithelial neoplasia (CINII), severe intraepithelial neoplasia(CINIII) and invasive cancer.

Cervical cancer can be classified into different types according todifferent standards.

According to whether cancer has metastasized or not, cervical cancer canbe divided into cancer in situ and invasive cancer. Cancer in situ ismore common in women aged 30-35, while invasive cancer is more common inwomen aged 45-55. Lymphatic metastasis may occur in patients with severecervical cancer. After local infiltration, the cancer invaded lymphaticvessels to form tumor plugs, which were drained into local lymph nodeswith lymph fluid and spread in lymphatic vessels.

According to pathological types, cervical cancer can be divided intothree types: squamous cell carcinoma, adenocarcinoma and adeno-squamouscarcinoma.

Cervical squamous cell carcinoma is the main type of cervical cancer.According to histological differentiation, it can be divided into threegrades: Grade I is highly differentiated squamous cell carcinoma, GradeII is medium differentiated squamous cell carcinoma (non-keratinizedlarge cell type), and Grade III is low-medium differentiated and lowdifferentiated squamous cell carcinoma (small cell type).

Cervical adenocarcinoma includes mucinous adenocarcinoma type andmalignant adenoma type. Mucinous adenocarcinoma originates from columnarmucous cells of cervical canal, and the glandular structure can be seenunder microscope. The hyperplasia of glandular epithelial cells ismultilayer, the dysplasia is obvious, and mitosis is seen. The cancercells protrude into the glandular cavity in mastoid shape. Malignantadenoma is a highly differentiated adenocarcinoma of cervical canalmucosa. There are many cancerous glands with different sizes and variedshapes, which extend into the deep cervical stroma in a punctate way.The glandular epithelial cells are atypical and often have lymph nodemetastasis.

Unexpectedly, the inventors found that peripheral red blood cellmicronuclei DNA can be used for screening and diagnosing cervicalcancer. The inventors further unexpectedly found that the micronucleiDNA of peripheral red blood cells can be used to distinguish the typesof cervical cancer, which can be divided into squamous cell carcinomaand adenocarcinoma. The inventor further unexpectedly found that,peripheral red blood cell micronuclei DNA can stage cervical cancer, forexample, cervical squamous cell carcinoma can be divided intohigh-differentiated type, medium-differentiated type, andlow-medium-differentiated and low-differentiated type. It is of greatsignificance for the early diagnosis, screening, classification andstaging of cervical cancer.

Colorectal Cancer

Colorectal cancer (CRC) is a cancer that arises from the colon orrectum. It is one of the most common malignant tumors in thegastrointestinal tract. The early symptoms are not obvious. The symptomsand signs shown with the increase of the cancer can include blood instools, weight loss, and constant fatigue (General Information AboutColon Cancer. NCI. May 12, 2014. Archived from the original on Jul. 4,2014. Retrieved Jun. 29, 2014).

There are approximately 1.4 million new cases of colorectal cancer eachyear. Colorectal cancer ranks third among newly diagnosed cancers, andit is also the fourth cause of death from cancer. Studies have shownthat by 2030, the number of global colorectal cancer cases is expectedto increase by 60%, with more than 2.2 million new cases per year andapproximately 1.1 million deaths per year (Global patterns and trends incolorectal cancer incidence and mortality. M, et al. Gut. 2017;66:683-91).

Globally, colorectal cancer is the third most common cancer, accountingfor about 10% of all cancer cases. It is especially common in developedcountries, where more than 65% of cases are found to be CRC, and it isusually less common in women than in men (Forman D, Ferlay J (2014).“Chapter 1.1: The global and regional burden of cancer”. In Stewart B W,Wild C P (eds.). World Cancer Report. the International Agency forResearch on Cancer, World Health Organization. pp. 16-53. ISBN978-92-832-0443-5).

With the improvement of people's living standards in China, theincidence of colorectal cancer is on the rise. The latest statisticsshow that the incidence and mortality of colorectal cancer (CRC) inChina have maintained an upward trend. Cancer statistics in China in2015 show that the incidence and mortality of colorectal cancer in mycountry rank fifth among all malignant tumors, with 376,000 new casesand 191,000 deaths. Among them, the amount in urban areas is much higherthan that in rural areas, and the incidence of colon cancer hasincreased significantly. Most patients are already in the middle andlate stages when found. Early diagnosis of colorectal cancer isextremely important, and early diagnosis can significantly increase thepossibility of successful treatment (5. Standards for Diagnosis andTreatment of Colorectal Cancer in China (2017 Edition) [J]. ChineseJournal of Medical Frontiers (Electronic Edition), 2018, 10(3): 1-21).

Causes of Disease

Most colorectal cancers are caused by factors like aging and lifestyle,and only a few cases are caused by potential hereditary diseases. Riskfactors include diet, obesity, smoking and lack of physical activity.Another risk factor is inflammatory bowel disease, including Crohn'sdisease and ulcerative colitis. Some hereditary diseases lead tocolorectal cancer, including familial adenomatous polyposis andhereditary nonpolyposis colon cancer. CRC usually begins with benigntumor and appears as polyp, which may become cancerous with time.

Classification

Classification According to Causes

According to the causes, colorectal cancer can be divided into threeclasses, two of which have genetic factors:

-   -   sporadic colorectal cancer (50% to 60%);    -   familial colorectal cancer (30% to 40%);    -   hereditary colorectal cancer (4% to 6%).

Sporadic colorectal cancer: Sporadic colorectal cancer is the mostcommon type, with 90% of patients diagnosed at the age of 50 and above.It is not directly related to genetics or family history. About one inevery 20 Americans has this type of CRC.

Familial colorectal cancer: Some families are prone to CRC. If more thanone person in the family suffers from CRC, especially before the age of50, attention must be paid to it. If immediate family members (parents,siblings or children) have colorectal cancer, the risk of such familymembers will double.

Hereditary colorectal cancer: At present, many hereditary diseases havebeen found to be related to CRC, including hereditary nonpolyposis coloncancer (HNPCC), also known as Lynch syndrome; Familial adenomatouspolyposis (FAP); Attenuated familial adenomatous polyposis (AFAP); APCI1307K; Potts-Jaggers syndrome; MYH-associated polyposis (MAP); Juvenilepolyposis; Hereditary polyposis.

Classification According to Focus of Cancer

According to the focus of cancer, colorectal cancer can be divided intocolon cancer and rectal cancer.

Importance of Early Screening

Lifestyles such as high-fat diet, smoking and alcoholism may increasethe risk of colorectal cancer. More than 90% of colorectal cancerpatients are over 50 years old. Usually, the best treatment period ismissed because of neglecting the early symptoms of the disease,including bloody feces or changes in defecation habits. Early diagnosiscan significantly increase the possibility of successful treatment.

In recent years, in the United States, the incidence rate and mortalityrate of CRC are gradually decreasing. The microscopic simulation modelMISCAN-Colon suggests that the observed mortality rate of CRC isdecreasing, and about 53% of it may benefit from CRC screening. In 2012,65.1% of adults at the age of 50-75 in the United States had beenscreened for CRC, and 27.7% had never been screened. Colonoscopy is themost frequently used screening examination (nearly 62%). From 2002 to2010, the screening rate increased from 52.3% to 65.4%. With theimprovement of screening rate, early treatment and intervention for riskindividuals significantly reduced the incidence rate and mortality rateof CRC (Cronin K A, Lake A J, Scott S, et al. Annual Report to theNation on the Status of Cancer, part I: National cancer statistics.Cancer 2018; 124:2785).

Early Screening and Diagnosis Methods of Colorectal Cancer in the PriorArt

Early screening and diagnosis of colorectal cancer mainly include thefollowing ways:

(1) Colonoscopy

Colonoscopy is the most accurate and universal diagnostic examination ofCRC, which can locate lesions in the whole large intestine and performbiopsy to find simultaneous tumors and remove polyps. Observed underendoscope, most colon cancer and rectal cancer are intraluminal masseswhich originate from mucosa and protrude into the lumen. Tumors can beexophytic or polypoid. Bleeding (blood oozing or obvious bleeding) maybe observed in fragile, necrotic or ulcerated lesions. A fewgastrointestinal tumor lesions (both asymptomatic and symptomaticindividuals) are non-polypoid. A study found that, non-polypoidcolorectal tumors are more prone to carcinogenesis than polypoid tumors.Compared with polypoid lesions, cancer caused by non-polypoid adenomamay be more difficult to be detected under colonoscopy, but colonoscopyis more sensitive to this situation than barium enema or CTcolonography. When experienced endoscopy operators use colonoscopy toexamine asymptomatic patients, the missed diagnosis rate of CRC is2%-6%.

(2) Flexible Sigmoidoscopy

It has been observed that in the past 50 years, the proportion of rightcolon cancer or proximal colon cancer in the United States and aroundthe world is gradually increasing, and the incidence of tumorsoriginating from cecum is increasing with the fastest speed. In view ofthis, and considering the high incidence of simultaneous CRC, forpatients with suspected CRC, flexible sigmoidoscopy is generallyconsidered not to be an appropriate diagnostic examination, unless thetumor is palpable in rectum. In this case, total colonoscopy is stillneeded to assess whether the rest of the colon has simultaneous polypsand cancer. However, flexible sigmoidoscopy is used to screen CRC. It isone of the few methods that have been proved by randomized controlledtrials to reduce the incidence and morbidity of CRC.

(3) CT Colonography

CT colonography, also known as virtual colonoscopy or CT colonography,can provide a computer-simulated intraluminal perspective for theinflated colon. This technology uses traditional spiral CT scanning orMRI to obtain a large number of continuous data, and uses complexpost-processing software to generate images, which can enable operatorsto walk and pass in any selected direction in the clean colon cavity. CTcolonography needs mechanical bowel preparation similar to barium enema,because feces can be similar to polyps in image, causing interference.CT colonography can also detect extracolonic lesions, which can provideinformation on the causes of symptoms and tumor staging, but it may alsolead to anxiety and increase costs due to unnecessary examinations. Andits detection rate for clinically important lesions may also be low.

Compared with colonoscopy, CT colonography is an alternative withsimilar sensitivity and less trauma for patients with CRC. However,considering that colonoscopy can remove/biopsy the lesions andsimultaneous cancers or polyps seen during the operation, colonoscopy isstill considered as the gold standard for CRC symptoms. When the use ofcolonoscopy is limited, CT colonography is preferred over barium enema(Mulder S A, Kranse R, Damhuis R A, et al. Prevalence and prognosis ofsynchronous colorectal cancer: a Dutch population-based study. CancerEpidemiol 2011; 35:442).

However, due to the particularity of sampling and testing methods, theabove screening methods will inevitably lead to psychological burden andlocal injury of some screeners, which is also an influencing factor thatlimits the long-term and large-scale screening, and it is necessary toconsider the adaptability of patients' age and screening methods.

(4) Guaiac-Based Faecal Occult Blood Test (gFOBT)

This test detects whether there is blood in a patient's stool sample.But blood stool test is not 100% accurate, because not all cancers causebleeding, or they may not bleed all the time. Therefore, this test cangive false negative results. Blood may also be present due to otherdiseases or conditions, such as hemorrhoids. The method of detectingfecal hemoglobin by guaiac is an indirect method for detectingperoxidase activity. There are non-hemoglobin peroxidase catalyticcomponents in various foods, which may cause false positive, thuslimiting the application of this method. Its advantage lies in theconvenience and rapidity of initial detection and screening, which hascertain guiding significance for further detection and diagnosis, butits accuracy is relatively low.

(5) Immunochemical Test (Faecal Immunochemical Test, FIT)

This test uses antibodies to detect fecal occult blood. FIT usesmonoclonal or polyclonal antibodies to directly detect hemoglobin inhuman feces, which is not affected by dietary. In qualitative FIT, colorchange is visible after the hemoglobin content in feces exceeds acertain threshold. While quantitative FIT can measure the value: when itexceeds a certain normal range, it is defined as positive. Compared withgFOBT, immunochemical test requires less stool samples, and there is nodietary restriction before collecting stool samples, but only one or twostool samples are collected each time (Mettle Kalager, et al.Overdiagnosis in Colorectal Cancer Screening: Time to Acknowledge aBlind Spot[J]. Gastroenterology, 2018 Aug. 1). Even if there is merelyoccult blood in a sample, occult blood can also be detected. Occultblood in a sample indicates intestinal bleeding. This method hasrelatively high specificity, but poor sensitivity, and there may also befalse positive or negative results due to interference from otherdiseases, which makes it impossible to make a definite diagnosis.

(6) Fecal DNA Test

Colorectal cancer generally occurs in colorectal epithelial tissue, andfirst grows into intestinal cavity. During its growth, tumor cells areconstantly shed into intestinal cavity and discharged with feces. Theshed tumor cells in feces contain special components (such as mutatedand methylated human genes), which can be used as tumor markers. FecalDNA test analyzed several DNA markers of colon cancer or precancerouspolyp cells flowing into feces. Patients can be provided with a kitcontaining instructions on how to collect stool samples at home, andthen send it to the laboratory for detection and analysis. This test ismore accurate for detecting colon cancer than polyp, but it cannotdetect all DNA mutations that indicate the existence of tumor. The valueof fecal gene detection lies in early diagnosis, which can prompt theoccurrence of colorectal cancer, find precancerous adenoma and helppatients to find colorectal cancer at an earlier stage (Imperiale, T.F., et al., Multitarget Stool DNA Testing for Colorectal-CancerScreening. New England Journal of Medicine, 2014. 370(14): p.1287-1297). However, fecal genetic testing can only be used as anauxiliary diagnostic method. If there is a positive result, it must beconfirmed and intervened by colonoscopy. However, due to the complexityof fecal DNA, its low specificity and low success rate of fecal DNApreparation will lead to insufficient cost-effectiveness, which greatlyhinders its practical application.

The above methods are relatively convenient for sampling, andnon-invasive. Non-invasive detection is more acceptable to patients,which may be used as an indicator of CRC screening. However, due to thespecificity and sensitivity of the methods, most of them can only beused as an auxiliary means of diagnosis, and other means such ascolonoscopy are still needed for diagnosis and intervention. Meanwhile,for stool sampling and treatment, the psychological burden to a certainextent, as well as the complexity and pollution of stool samples, alsocause problems in the stability and repeatability of sample detection(Brenner, H., et al., Prevention, Early Detection, and Overdiagnosis ofColorectal Cancer Within 10 Years of Screening Colonoscopy in Germany.Clinical Gastroenterology and Hepatology, 2015. 13(4): p. 717-723).Therefore, a more reliable and stable sample source is needed to providea more dynamic, accurate and instructive monitoring system for CRCscreening.

Surprisingly, the inventors found that peripheral red blood cellmicronuclei DNA can be used to screen and diagnose colorectal cancer.The inventors further surprisingly found that micronuclei DNA ofperipheral red blood cells can be used to distinguish the types ofcolorectal cancer, which can be divided into colon cancer and rectalcancer. It is of great significance for early diagnosis, screening andrisk ranking of colorectal cancer.

Lung Cancer

Lung cancer is the most common cancer type worldwide in terms of bothincidence and mortality. The key cause of lung cancer is tobaccosmoking, which is responsible for 63% of overall global deaths from lungcancer and for more than 90% of lung cancer deaths in countries wheresmoking is prevalent in both sexes. Causes of lung cancer alsoincluding: secondhand smoke, family history of lung cancer, exposed toasbestos, arsenic, chromium, beryllium, nickel, soot, or tar in theworkplace, air population, etc.

Classification according to causes:

According to the causes, lung cancer can be divided into two mainclasses are small-cell lung carcinoma (SCLC) and non-small-cell lungcarcinoma (NSCLC).

SCLC (10%-15%): This type of lung cancer is the most aggressive andrapidly growing of all the types. SCLC is strongly related to cigarettesmoking. SCLCs metastasize rapidly to many sites within the body and aremost often discovered after they have spread extensively.

NSCLC (85%): NSCLC has three main types designated by the type of cellsfound in the tumor. They are:

-   -   Adenocarcinomas (40%), while adenocarcinomas are associated with        smoking like other lung cancers, this type is also seen in        non-smokers—especially women—who develop lung cancer.        Adenocarcinoma in situ (previously called bronchioloalveolar        carcinoma) is a subtype of adenocarcinoma that frequently        develops at multiple sites in the lungs and spreads along the        preexisting alveolar walls. It may also look like pneumonia on a        chest X-ray. It is increasing in frequency and is more common in        women. People with this type of lung cancer tend to have a        better prognosis than those with other types of lung cancer;    -   Squamous cell carcinomas (25%-30%), squamous cell cancers arise        most frequently in the central chest area in the bronchi. This        type of lung cancer most often stays within the lung, spreads to        lymph nodes, and grows quite large, forming a cavity;    -   Large cell carcinomas (10%-15%), this type of cancer has a high        tendency to spread to the lymph nodes and distant sites.        Other types of cancers can arise in the lung; these types are        much less common than NSCLC and SCLC and together comprise only        5%-10% of lung cancers.

The Diagnosis of Lung Cancer is Mainly Focused on Imaging Examination:

(1) X-ray inspection: X-ray examination can understand the location andsize of lung cancer, and may see local emphysema, atelectasis, orinfiltrating lesions or pulmonary inflammation near the lesion due tobronchial obstruction. (2) Bronchoscopy: the bronchoscope can directlyobserve the pathological conditions of the bronchial lining and lumen.Tumor tissue can be taken for pathological examination, or bronchialsecretions can be drawn for cytological examination to confirm thediagnosis and determine the histological type. (3) Cytologicalexamination: sputum cytology is a simple and effective method forgeneral screening and diagnosis of lung cancer. Most patients withprimary lung cancer can find shed cancer cells in the sputum. Thepositive rate of sputum cytology for central lung cancer can reach 70%to 90%, while that for peripheral lung cancer is only about 50%. (4) ECTinspection:ECT bone imaging can detect bone metastases earlier. BothX-ray film and bone imaging have positive findings. If the osteogenesisreaction of the lesion is static and the metabolism is not active, thebone imaging is negative and the X-ray film is positive. The twocomplement each other and can improve the diagnosis rate. (6)Mediastinoscopy: mediastinoscopy is mainly used for patients withmediastinal lymph node metastasis, which is not suitable for surgicaltreatment, and other methods cannot obtain pathological diagnosis.

Surprisingly, the inventors found that peripheral red blood cellmicronuclei DNA (rbcDNA) can be used to screen and diagnose lung cancer.The inventors further surprisingly found that rbcDNA signature is ofgreat significance for early diagnosis, screening and risk ranking oflung cancer.

Hepatocellular Cancer

Hepatocellular cancer (HCC) is the fifth most common cause of cancer,and the incidence is increasing globally due to the spread of hepatitisB and C virus infections, causes also including: cirrhosis, heavydrinking, obesity and diabetes, abusive anabolic steroids, iron storagedisease and aflatoxin. If caught early, it can sometimes be cured bysurgery or transplantation. In more severe cases, it cannot be cured.

Detection of Serum Bio-Markers for Hepatocellular Cancer

(1) The determination of serum alpha-fetoprotein (AFP) is relativelyspecific for the diagnosis of this disease. Immunoassay measurescontinuous serum AFP≥400 μg/L, and can rule out pregnancy, active liverdisease, etc., then the diagnosis of liver cancer can be considered.However, approximately 30% of patients with liver cancer are clinicallynegative for AFP. (2) Blood enzymology and other tumor markerexaminations. The levels of γ-glutamyl transpeptidase and itsisoenzymes, abnormal prothrombin, alkaline phosphatase, and lactatedehydrogenase isoenzymes in the serum of patients with liver cancer maybe higher than normal, but it lacks specificity.

Imaging Examination

(1) Ultrasound examination can show the size, shape, location of thetumor and whether there are tumor thrombi in the hepatic vein or portalvein, and the diagnostic coincidence rate can reach 90%. (2) CTexamination has a high resolution, and the diagnostic coincidence ratefor liver cancer can reach more than 90%, and it can detect small cancerfoci with a diameter of about 1.0 cm. (3) The diagnostic value of MRI issimilar to that of CT. It is better than CT in distinguishing benign andmalignant intrahepatic lesions, especially from hemangioma. (4)Selective angiography of celiac artery or hepatic arteriography. Forcancers with abundant blood vessels, but the low-resolution limit forsmall liver cancers tumor volume less than 2.0 cm, the positive rate canreach 90%. (5) Needle aspiration cytology for liver puncture, needleaspiration under the guidance of B-mode ultrasound can help increase thepositive rate in cancer diagnosis, but with invasive tissue damage.

Surprisingly, the inventors found that peripheral red blood cellmicronuclei DNA (rbcDNA) can be used to screen and diagnosehepatocellular cancer. The inventors further surprisingly found thatrbcDNA signature is of great significance for early diagnosis, screeningand risk ranking of hepatocellular cancer.

Combined Application of the Invention and Other Methods

In certain embodiments, the methods of the present disclosure can alsobe combined with other methods for screening, diagnosing or risk rankingof cancer. Those skilled in the art can select suitable other methods inthe prior art as required.

In certain embodiments, methods related to cervical cancer that can becombined with the methods of the present disclosure include, forexample, detection of high-risk HPV and cytological examination ofcervical exfoliated cells. In an embodiment, the detection methods forhigh-risk HPV include morphological observation method,immunohistochemistry method, dot-blot hybridization method, blottinghybridization in situ, PCR/RFLP method, PCR/Southern method and thelike. In one embodiment, the cytological examination of cervicalexfoliated cells includes TCT, Pap smear, etc.

In certain embodiments, methods related to colorectal cancer that can becombined with the methods of the present disclosure include, forexample, colonoscopy, flexible sigmoidoscopy, CT colonography, fecaloccult blood test, immunochemical test, fecal DNA test, and the like.

EXAMPLES

In the following section, the present invention is further illustratedby examples. Examples are provided by way of illustration, but thepresent invention is not limited to the following examples. In thefollowing examples, the subjects are all human subjects.

Example 1: Density Gradient Centrifugation of Peripheral Blood

Through the following steps, the peripheral blood samples of eachsubject were subjected to density gradient centrifugation.

Step 1. 1 ml fresh peripheral blood was obtained from a subject, and1×PBS was added in equal volume to prepare a diluted blood sample.

Step 2. 5 ml Ficoll density gradient centrifuge (Stemcell, Lymphoprep™07801) was added into the density gradient centrifuge tube.

Step 3. The diluted blood sample prepared in step 1 was slowly added tothe density gradient centrifuge tube in Step 2. Density gradientcentrifugation was performed at 1200 g at 18° C. for 15 minutes.

After density gradient centrifugation, the sample was divided into threelayers: the upper layer was plasma, the middle layer was peripheralblood mononuclear cells (PBMC), and the bottom layer was red blood cells(as shown in FIG. 1 ).

Example 2: Separation of Blood Cells

After density gradient centrifugation in Example 1, peripheral bloodmononuclear cells and red blood cells were separated.

Specifically, as shown in FIG. 2 , the middle-upper layer liquid in thedensity gradient centrifuge tube was sucked through a straw, and theperipheral blood mononuclear cell sample was separated and collected.Red blood cells were extracted from the bottom of density gradientcentrifuge tube via a needle tube, added into a 1.5 ml centrifuge tube.1×PBS was added into the centrifuge tube to a volume of 1 ml liquid.Centrifugation was proceeded at room temperature for 10 min at 300 g,and red blood cells at the bottom of the tube were collected. Thecollected RBCs were then subject to two sequential filtrations by 10 μmcell strainers to remove potential contamination of nucleated cells.

Example 3: DNA Extraction

In this example, the genome of peripheral blood mononuclear cells anderythrocyte micronuclei DNA were extracted, respectively.

3.1 Extraction of Genomic DNA from Peripheral Blood Mononuclear Cells

Genomic DNA was extracted from the peripheral blood mononuclear cellsample obtained in Example 2 using QIAamp DNA Blood Mini Kit (Qiagen,Cat No./ID: 51106), as shown in FIG. 3 .

3.2 Extraction of Erythrocyte Micronuclei DNA

Red blood cells obtained in Example 2 were lysed by a red blood celllysis buffer. Specifically, 10 ml of red blood cell lysis buffer(Biosharp, Cat No./ID: BL503B) was added to the red blood cellscollected in Example 2, lysed for 20 minutes at room temperature in thedark, and centrifuged at 3000 g at room temperature for 10 minutes.Supernatant was taken and incubated with 10 mm EDTA (Solarbio CatNo./ID: E1170) and 200 ug/ul protease K (Ambion, Cat No./ID: AM2548) at56° C. for 8 hours. Erythrocyte micronuclei DNA was extracted usingQIAamp DNA Blood Mini Kit (Qiagen, Cat No./ID: 51106).

Example 4: DNA Amplification, Library Construction and Sequencing

Genomic DNA of peripheral blood mononuclear cells and erythrocytemicronuclei DNA extracted in Example 3 were amplified, libraryconstructed and sequenced, respectively.

4.1 DNA Amplification

Genomic DNA of peripheral blood mononuclear cells and erythrocyteMicronuclei DNA prepared in Example 3 were subjected to multipledisplacement amplification (MDA) using REPLI-g Single Cell Kit(Qiagen,Cat No./ID: 150345), to obtain amplified DNA samples.

4.2 Library Construction

After MDA, the amplified DNA samples were subjected to second-generationsequencing library construction using TruePrep DNA Library Prep Kit V2for Illumina (Vazyme, TD503).

4.3 High-Throughput Sequencing

Genomic DNA of peripheral blood mononuclear cells and erythrocytemicronuclei DNA were sequenced by Novo-seq platform, with 10×sequencingdepth and 30 G data.

Example 5: Bioinformatics Analysis of Erythrocyte Micronuclei DNA andGenomic DNA of Peripheral Blood Mononuclear Cells

Bioinformatics analysis was made on micronuclei DNA information in redblood cells by the following steps (see FIG. 4 for the logic ofbioinformatics analysis algorithm):

1. Quality control. Quality control on the original sequencing files ofdouble-ended sequencing of erythrocyte micronuclei DNA and peripheralblood mononuclear cell genome DNA respectively through FastQC software.

2. Adaptor removal. Adaptor removal in the original sequencing filethrough cutadapter software (Kong, Y., Btrim: a fast, lightweightadapter and quality trimming program for next-generation sequencingtechnologies. Genomics, 2011. 98(2): p. 152-3). According to sequencingquality, the reads of small fragments with appropriate length andaccurate pairing were reserved.

3. Data alignment. Sequenced fragments of red blood cell micronuclei DNAand peripheral blood mononuclear cell genome DNA were analyzed by bwasoftware (http://bio-bwa.sourceforge.net) was aligned to the humangenome, and inappropriate and repeated reads were removed by Picard(Weisenfeld, N. I., et al., Direct determination of diploid genomesequences. Genome Res, 2017. 27(5): p. 757-767).

4. Comparison and counting of reads. The reads of sequenced smallfragments in erythrocyte micronuclei DNA were counted corresponding tothe gene regions of human genome using htseq-count software (Anders, S.,P. T. Pyl and W. Huber, HTSeq-a Python framework to work withhigh-throughput sequencing data. Bioinformatics, 2015. 31(2): p. 166-9),to compare whether there were significant differences in the degree ofDNA fragmentation in red blood cells of healthy individuals and cancerpatients.

5. Peak Calling. Searching for the fragments of red blood cellmicronuclei DNA which were mainly enriched in a specific genetic regionrelative to the genome DNA sequencing reads of peripheral bloodmononuclear cells through macs2 software, and removing the peak areaswhich were more enriched by peripheral blood mononuclear cells relativeto PBMC per se as a whole.

6. Genome information annotation and pathway enrichment of specificbroken fragments in erythrocyte micronuclei DNA. Compared withperipheral blood mononuclear cells, genome information annotation andpathway enrichment (KEGG, Gene Ontology) were performed on specificbroken fragments of erythrocytes (Chen, L., et al., Gene Ontology andKEGG Pathway Enrichment Analysis of a Drug Target-Based ClassificationSystem. PLoS One, 2015. 10(5): p. e0126492), the specific broken genesin erythrocyte micronuclei DNA were obtained.

7. Data classification and classifier construction. Differentiated geneswere select as features to construct classifiers for known classifiedsamples based on support vector machine (SVM), and to predict unknownsamples (Huang, M. W., et al., SVM and SVM Ensembles in Breast CancerPrediction. PLoS One, 2017. 12(1): p. e0161501).

7.1 Data Classification

Specifically, the reads count in gene regions of “n” experimentalsamples and “m” control samples were selected every time, wherein “n”and “m” refers to the number of samples). The differentiated genes (alsocalled “characteristic genes”) were screened out by ANOVA test todistinguish the two types of samples.

7.2 Classifier Construction

Classifier parameter adjustment. Based on the characteristic genesscreened in step 7.1, the training group (n=100) was determined by usingthe algorithm SVM/LOOCV (leave-one-out cross-validation support vectormachine). First, the true labels of all samples were set (e.g., thesample in the experimental group was recorded as 1, and the sample inthe control group was recorded as 0). One sample was picked out at atime as a test set, and all other samples (n−1) were used to build amodel and test the “test set”. The test set traversed all samples tocomplete n rounds of cross-validation, and the test results for eachsample were obtained. Based on the whole test results and the real labelof each sample, the accuracy, sensitivity and specificity werecalculated, so as to adjust the best parameters of the model andconstruct the training model. In this study, the parameters of SVM wereset as C=100 and gamma=10⁻⁴, wherein C is the penalty coefficient, thatis, the tolerance of errors; gamma is a default parameter when RBFfunction is selected as kernel.

7.3 Prediction on Unknown Samples

Based on the training model obtained in the previous step, unknownsamples (i.e., test sets) that did not participate in the training wereused to predict the test set samples through the classifier constructedin the previous step, to obtain the prediction results of the test setand the real labels of the samples, and to present the proportion ofeach prediction result in the two classes (i.e., risk assessment index).Unknown samples were predicted and to show the results of binaryclassification.

Example 6: Construction of a Classifier for Clustering HealthyIndividuals and Cervical Cancer Patients Using Erythrocyte MicronucleiDNA

In this example, there were 15 subjects, including:

Experimental group: 9 patients diagnosed with cervical cancer by othermethods

Control group: 6 healthy individuals (non-cervical disease individuals).

The peripheral blood samples from patients with cervical cancer wereexpressed in the form of “P” plus patient number. For example, “P1”represented a peripheral blood sample from the first cervical cancerpatient (“Patient 1”), “P2” represented a peripheral blood sample fromthe second cervical cancer patient (“Patient 2”), and so on. Inaddition, peripheral blood samples from healthy individuals wereexpressed in the form of “H” plus individual number. For example, “H1”represents the peripheral blood sample from the first healthyindividual, “H2” represents the peripheral blood sample from the secondhealthy individual, and so on.

The basic information of 9 patients with cervical cancer is shown inTable 1. “cervical cancer type” refers to the type of cervical cancerdiagnosed by other methods.

TABLE 1 HPV Maximum Patient Detected diameter of Existence of lymphnumber Age value tumor (cm) Type of cervical cancer node metastasis ornot 1 65 25.55 3.3 Medium differentiated No squamous cell carcinoma 2 3650.13 4.2 Low-medium differentiated No adenocarcinoma 3 36 916.-3 4.0CINIII budding growth Not dissected (early invasion of cancer) 4 43240.09 4.1 Low differentiated Yes (without surgery) squamous cellcarcinoma 5 5 3.67 3.7 Non-invasive carcinoma Not dissected 6 56 503.613.2 Low-medium differentiated No squamous cell carcinoma 7 71 1212.8 2.6Medium differentiated Yes (without surgery) squamous cell carcinoma  8*37 No 5.4 Low-medium differentiated Yes squamous cell carcinoma 9 4468.36 2.1 Medium-high differentiated No adenocarcinoma *Patient 8 is HPVnegative.

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Specifically, 9 samples of primary cervical cancer and 6 samples ofhealthy women were selected for the reads counting, and 2306differential genes were screened out by ANOVA test to distinguish thetwo classes of samples. Then, according to Pearson correlation, the twoclasses of samples were clustered in unsupervised hierarchy, showingthat there were significant differences between the two classes ofsamples.

As shown in FIG. 5 , the erythrocyte micronuclei DNA from the peripheralblood samples of cervical cancer patients and the erythrocytemicronuclei DNA from the peripheral blood samples of healthy individualswere clustered to obtain 2,306 differential genes (forming a classifierfor distinguishing healthy individuals from cervical cancer patients).In FIG. 5 , each row represents a differential gene, and each columnrepresents a patient.

The list of 2,306 differential genes is shown in Table 2. Each genecorresponds to each row from top to bottom in FIG. 5 .

TABLE 2 1 A2MP1 2 ABCA11P 3 ABCA9-AS1 4 ABCB7 5 ABCG4 6 ABCG5 7 ABHD3 8ABRAXAS1 9 ACADM 10 ACAN 11 ACAP2 12 ACAT2 13 ACKR3 14 ACKR4 15 ACOD1 16ACP7 17 ACSM5 18 ACTR1B 19 ACTR3C 20 ACTR6 21 ADAM21 22 ADAM30 23 ADAT124 ADCY2 25 ADCY6 26 ADCY9 27 ADD3-AS1 28 ADPGK 29 ADRB1 30 AFDN-DT 31AFG1L 32 AFTPH 33 AGAP4 34 AGFG1 35 AGO2 36 AGPAT1 37 AGPAT3 38 AIMP1 39AIPL1 40 AK4 41 AKAIN1 42 AKAP11 43 AKAP5 44 AKIRIN1 45 AKR1C4 46 AKTIP47 ALDH3A2 48 ALKBH8 49 AMMECR1 50 AMPH 51 ANGPT2 52 ANKRD13C 53ANKRD18DP 54 ANKRD20A19P 55 ANKRD36BP1 56 ANKRD62P1-PARP4P3 57 ANKS4B 58ANXA2P1 59 AP3D1 60 AP3M2 61 AP4S1 62 APOBEC1 63 APOBEC4 64 APOL4 65APOL6 66 APOLD1 67 ARAP1 68 ARF4-AS1 69 AREGAP2 70 ARFGEF1 71ARHGAP22-IT1 72 ARHGAP26-AS1 73 ARHGAP36 74 ARHGEF11 75 ARHGEF7 76ARID1B 77 ARL11 78 ARL2BP 79 ARL6IP1 80 ARMC6 81 ARMCX5 82 ARPC1B 83ARPP19 84 ARSJ 85 ASB10 86 ASB3 87 ASIC4 88 ATP13A3 89 ATP2B1-AS1 90ATP5F1C 91 ATP5PO 92 ATP6V0A4 93 ATP7A 94 ATXN7L3B 95 AUNIP 96 AWAT1 97AXIN2 98 B3GALNT1 99 B3GNT5 100 BAG2 101 BBS1 102 BBS2 103 BBS9 104 BEX1105 BEX5 106 BFSP1 107 BHLHE40-AS1 108 BICRAL 109 BIRC6-AS2 110 BLOC1S2111 BLVRB 112 BMP15 113 BMS1 114 BORA 115 BRMS1L 116 BRWD1-AS1 117 BSND118 BTBD3 119 BTBD9-AS1 120 BTG1 121 BTG2 122 BTG4 123 BTN2A2 124 BTN3A2125 BTNL2 126 BUD31 127 C10orf143 128 C11orf44 129 C11orf53 130 C11orf54131 C12orf10 132 C12orf45 133 C12orf71 134 C12orf75 135 C14orf39 136C16orf89 137 C17orf75 138 C18orf54 139 C19orf66 140 C1GALT1 141 C1QTNF6142 C1S 143 C1orf68 144 C21orf59 145 C2orf48 146 C2orf49 147 C2orf74 148C2orf78 149 C3orf18 150 C3orf38 151 C4orf45 152 C4orf47 153 C5orf24 154C5orf64 155 C5orf66 156 C6orf99 157 C7orf13 158 C7orf26 159 C8orf31 160C8orf48 161 C9orf170 162 C9orf40 163 C9orf43 164 C9orf66 165 C9orf92 166CA2 167 CA8 168 CACNA1I 169 CACNB3 170 CADM4 171 CALCRL 172 CAMK1G 173CASC1 174 CASC3 175 CASC9 176 CAVIN4 177 CBWD5 178 CBX2 179 CBX3 180CBX5 181 CC2D1B 182 CCDC120 183 CCDC121 184 CCDC152 185 CCDC17 186CCDC18-AS1 187 CCDC186 188 CCDC89 189 CCEPR 190 CCIN 191 CCL11 192 CCL22193 CCL5 194 CCNG1 195 CCNI2 196 CCNT2 197 CCNT2-AS1 198 CCR5 199 CCT2200 CCT6A 201 CCT8 202 CD160 203 CD28 204 CD300LB 205 CD33 206 CD37 207CD3E 208 CD40 209 CD40LG 210 CD58 211 CD72 212 CDC40 213 CDCA3 214 CDCP1215 CDH5 216 CDK13 217 CDKN2B 218 CDSN 219 CDV3 220 CENPL 221 CEP78 222CEP83-AS1 223 CETN1 224 CFAP126 225 CFAP77 226 CFAP97 227 CFDP1 228CFHR4 229 CHAMP1 230 CHIC1 231 CHMP4B 232 CHRNA10 233 CKAP5 234 CLDN19235 CLDN22 236 CLDN7 237 CLDND1 238 CLEC1B 239 CLEC2B 240 CLEC5A 241CLK2P1 242 CLRN1 243 CLRN3 244 CLSTN2-AS1 245 CLTA 246 CLTB 247 CLUL1248 CMC1 249 CMC2 250 CNBP 251 CNDP2 252 CNGA1 253 CNGA4 254 CNIH4 255CNKSR3 256 CNOT6L 257 CNP 258 COG4 259 COG8 260 COL6A4P1 261 COMMD6 262COPB2 263 COX7A2L 264 CPB1 265 CPEB1 266 CPHXL 267 CPLX2 268 CPNE6 269CREB1 270 CRH 271 CRIPT 272 CRISPLD1 273 CRNN 274 CRYBG2 275 CRYM 276CSF1R 277 CST1 278 CST3 279 CST9 280 CT62 281 CTHRC1 282 CTIF 283 CTSO284 CTSV 285 CTXND1 286 CTXND2 287 CUL7 288 CXCL3 289 CXCL5 290 CXCL6291 CXCL9 292 CXCR4 293 CYB5D2 294 CYP11B1 295 CYP27C1 296 CYP4V2 297CYP4Z1 298 CYP4Z2P 299 CYP8B1 300 CYTH3 301 CYTH4 302 CYYR1 303 DACT1304 DACT3-AS1 305 DAGLB 306 DARS-AS1 307 DAZL 308 DBF4 309 DBT 310 DBX2311 DCAF12L1 312 DCAF12L2 313 DCK 314 DCLRE1A 315 DCPS 316 DCTN1-AS1 317DDB2 318 DDI1 319 DDX42 320 DEFA5 321 DEFA9P 322 DENND1B 323 DENND1C 324DENND2A 325 DEPDC1-AS1 326 DEPDC1B 327 DGCR5 328 DGUOK 329 DHRS4-AS1 330DIRC3 331 DIS3 332 DKFZP586I1420 333 DKK2 334 DLG3 335 DMWD 336 DNAAF3337 DNAI1 338 DNAJA3 339 DNAJC27 340 DNAJC5G 341 DNAJC6 342 DNM1P46 343DNM3-IT1 344 DNMT1 345 DNPH1 346 DPM1 347 DPP10-AS1 348 DPPA2P3 349DPRXP4 350 DPY19L2P1 351 DPYD-AS2 352 DPYS 353 DR1 354 DRAIC 355 DSTYK356 DTX3L 357 DUOXA1 358 DUSP18 359 DUSP21 360 DUSP5 361 DYNC1LI2 362DYNLRB2 363 DYRK2 364 EAF2 365 ECHDC2 366 EDRF1 367 EFNA2 368 EIF2D 369EIF2S2 370 EIF2S3L 371 EIF3B 372 EIF3J 373 EIF5A2 374 EIF6 375 ELAVL1376 ELMOD2 377 ELOA2 378 ELSPBP1 379 EMB 380 EML6 381 EMP1 382 EMX1 383ENG 384 ENOPH1 385 ENTPD3-AS1 386 ENTPD6 387 EPB41L4A-AS1 388 EPB41L4B389 EPB41L5 390 EPCAM 391 EPHA10 392 EPN2 393 ERCC1 394 ERGIC2 395ERICH2 396 ERICH3-AS1 397 ERN2 398 ERVV-1 399 ERVW-1 400 ESCO2 401 ESX1402 ETFBKMT 403 ETNPPL 404 ETS2 405 ETV4 406 EWSAT1 407 EXOC5 408 EXOC6B409 EXOSC7 410 EXPH5 411 EXTL1 412 EXTL3 413 EZR 414 FABP4 415 FAM105A416 FAM111A-DT 417 FAM117B 418 FAM124B 419 FAM131A 420 FAM161B 421FAM162B 422 FAM183A 423 FAM196B 424 FAM199X 425 FAM19A3 426 FAM200B 427FAM201A 428 FAM205C 429 FAM212B 430 FAM217A 431 FAM228B 432 FAM238B 433FAM238C 434 FAM24A 435 FAM45BP 436 FAM47A 437 FAM69A 438 FAM76A 439FAM83C 440 FAM87B 441 FAM90A1 442 FAM92A 443 FAM98B 444 FAM9C 445FASTKD5 446 FBXL14 447 FBXL2 448 FBXL4 449 FBXO15 450 FBXO4 451 FBXO40452 FBXO45 453 FBXW2 454 FCER1G 455 FCN3 456 FCRL2 457 FCRL3 458 FCRLA459 FCRLB 460 FECH 461 FEZ2 462 FEZF1-AS1 463 FGD3 464 FGF12-AS2 465FGF9 466 FGFBP3 467 FGFR1OP 468 FGG 469 FGL2 470 FHAD1 471 FHL5 472FILIP1L 473 FJX1 474 FLG2 475 FLJ12825 476 FLJ31104 477 FLJ37201 478FLJ42393 479 FOLR2 480 FOXP1-AS1 481 FRZB 482 FSHB 483 FSTL5 484 FTSJ3485 FTX 486 FUNDC2P2 487 FUT8-AS1 488 FUT9 489 FXN 490 FZD3 491 FZD4 492FZD7 493 GABARAPL3 494 GABRA5 495 GART 496 GAS1 497 GATA1 498 GATA6 499GBA2 500 GBP1 501 GBP6 502 GCH1 503 GDPD2 504 GEN1 505 GGPS1 506 GGT7507 GHRLOS 508 GID8 509 GIMAP1 510 GIMAP7 511 GIMAP8 512 GINM1 513 GIPC1514 GJA10 515 GJA3 516 GJD3 517 GKN2 518 GLI3 519 GLS 520 GLT8D1 521GLYR1 522 GMFB 523 GMPPA 524 GNAI3 525 GNPDA1 526 GOLGA8J 527 GOLIM4 528GOLPH3L 529 GON7 530 GORASP2 531 GOT2 532 GP1BA 533 GP6 534 GPALPP1 535GPR1-AS 536 GPR141 537 GPR142 538 GPR149 539 GPR52 540 GPR6 541 GPR75542 GPR82 543 GRHL1 544 GRIN2D 545 GRIPAP1 546 GSK3B 547 GSN 548 GSN-AS1549 GTF3C3 550 GTSE1-AS1 551 GUCA1C 552 GYPE 553 GZF1 554 H1FNT 555H3F3B 556 HAAO 557 HAND1 558 HAS3 559 HBB 560 HBP1 561 HCCS 562 HCFC2563 HCG24 564 HCG9 565 HCRTR2 566 HEATR1 567 HEYL 568 HHAT 569 HIF1A-AS1570 HIGD1B 571 HIKESHI 572 HINT2 573 HINT3 574 HIST1H2AL 575 HIST1H2BA576 HIST1H2BD 577 HIST1H4F 578 HLA-DOA 579 HLA-DOB 580 HLA-DPB1 581HLA-DQB2 582 HLA-F 583 HLTF 584 HMGA1P7 585 HMGN5 586 HMGXB3 587 HNF1A588 HNRNPA1P10 589 HNRNPA3 590 HNRNPD 591 HNRNPDL 592 HNRNPL 593 HNRNPU594 HOOK3 595 HOTAIRM1 596 HOXC8 597 HPCAL4 598 HPS6 599 HRASLS 600HRASLS2 601 HRC 602 HS3ST3B1 603 HSD3BP4 604 HSD52 605 HSDL1 606 HSDL2607 HSF2 608 HSPA14 609 HSPA9 610 HTATIP2 611 HTR1A 612 HTR1D 613 HTR3D614 HYALP1 615 HYKK 616 IAPP 617 ICE1 618 IDS 619 IFT20 620 IFT88 621IGFBP1 622 IGFL3 623 IGLL5 624 IGSF9B 625 IL10RB-AS1 626 IL13 627 IL17RC628 IL17RE 629 IL20RB 630 IL21 631 IL33 632 IL4R 633 IL6 634 IL6R 635INE2 636 ING4 637 INHBA 638 IPO8 639 IQCA1 640 IQCF2 641 IQGAP2 642IRAK1BP1 643 IRS2 644 ISLR2 645 ISM1 646 ISOC1 647 ITFG1-AS1 648 ITFG2649 ITGAL 650 ITGAV 651 ITGB3BP 652 IWS1 653 JADE3 654 JAM3 655JMJD1C-AS1 656 JRK 657 KANSL3 658 KATNBL1P6 659 KBTBD13 660 KC6 661KCNA3 662 KCNH1-IT1 663 KCNJ1 664 KCNJ13 665 KCNK3 666 KCNK5 667 KCNMB3668 KCNS1 669 KCTD21 670 KCTD9 671 KDELC1 672 KDM4A-AS1 673 KIAA0754 674KIAA0895L 675 KIAA2026 676 KIF20A 677 KIF4B 678 KIF6 679 KIRREL3-AS3 680KLF11 681 KLF12 682 KLF13 683 KLF3 684 KLHDC1 685 KLHL34 686 KLK11 687KLK2 688 KLLN 689 KLRB1 690 KLRC1 691 KLRF2 692 KLRG1 693 KMT2E-AS1 694KPNA6 695 KPRP 696 KRBA2 697 KRCC1 698 KRIT1 699 KRT10 700 KRT13 701KRT25 702 KRT4 703 KRT6B 704 KRT83 705 KRTAP12-2 706 KRTAP17-1 707KRTAP19-2 708 KRTAP20-1 709 KRTAP4-5 710 KRTAP5-2 711 KRTAP5-AS1 712KRTAP9-4 713 KRTDAP 714 LAMP5 715 LAMP5-AS1 716 LAMTOR5-AS1 717 LAPTM4B718 LATS1 719 LCORL 720 LCP2 721 LDLRAD4-AS1 722 LEF1-AS1 723 LGALS13724 LGALS17A 725 LGALS3 726 LGALS8-AS1 727 LIMD1-AS1 728 LIMK2 729LINC00161 730 LINC00216 731 LINC00240 732 LINC00308 733 LINC00309 734LINC00317 735 LINC00331 736 LINC00339 737 LINC00363 738 LINC00392 739LINC00440 740 LINC00467 741 LINC00491 742 LINC00520 743 LINC00539 744LINC00548 745 LINC00615 746 LINC00620 747 LINC00626 748 LINC00628 749LINC00641 750 LINC00668 751 LINC00674 752 LINC00837 753 LINC00844 754LINC00862 755 LINC00889 756 LINC00901 757 LINC00924 758 LINC00926 759LINC00970 760 LINC00987 761 LINC00999 762 LINC01012 763 LINC01016 764LINC01036 765 LINC01037 766 LINC01039 767 LINC01049 768 LINC01099 769LINC01121 770 LINC01135 771 LINC01140 772 LINC01191 773 LINC01202 774LINC01209 775 LINC01224 776 LINC01243 777 LINC01305 778 LINC01340 779LINC01370 780 LINC01416 781 LINC01432 782 LINC01461 783 LINC01474 784LINC01476 785 LINC01478 786 LINC01486 787 LINC01499 788 LINC01564 789LINC01565 790 LINC01580 791 LINC01586 792 LINC01594 793 LINC01600 794LINC01623 795 LINC01628 796 LINC01657 797 LINC01682 798 LINC01683 799LINC01695 800 LINC01698 801 LINC01721 802 LINC01723 803 LINC01725 804LINC01737 805 LINC01846 806 LINC01851 807 LINC01877 808 LINC01878 809LINC01907 810 LINC01915 811 LINC01933 812 LINC01934 813 LINC01939 814LINC01959 815 LINC01975 816 LINC01985 817 LINC01986 818 LINC01990 819LINC01991 820 LINC02009 821 LINC02010 822 LINC02020 823 LINC02041 824LINC02049 825 LINC02071 826 LINC02106 827 LINC02120 828 LINC02135 829LINC02149 830 LINC02158 831 LINC02167 832 LINC02185 833 LINC02210 834LINC02217 835 LINC02226 836 LINC02233 837 LINC02278 838 LINC02287 839LINC02292 840 LINC02303 841 LINC02314 842 LINC02324 843 LINC02339 844LINC02363 845 LINC02365 845 LINC02376 847 LINC02380 848 LINC02382 849LINC02387 850 LINC02414 851 LINC02431 852 LINC02454 853 LINC02485 854LINC02488 855 LINC02523 856 LINC02542 857 LINC02544 858 LINC02565 859LIPJ 860 LIVAR 861 LMCD1-AS1 862 LMNTD1 863 LMO4 864 LNX1-AS1 865LOC100128594 866 LOC100129138 867 LOC100129148 868 LOC100129297 869LOC100129636 870 LOC100129935 871 LOCIOO130075 872 LOC100130298 873LOC100132831 874 LOC100192426 875 LOC100240728 876 LOC100270746 877LOC100270804 878 LOC100272217 879 LOC100287467 880 LOC100287497 881LOC100288637 882 LOC100288842 883 LOC100289230 884 LOC100289495 885LOC100335030 886 LOC100500773 887 LOC100505978 888 LOC100506098 889LOC100506302 890 LOC100506358 891 LOC100506497 892 LOC100506548 893LOC100506682 894 LOC100507002 895 LOC100507388 896 LOC100508631 897LOC100996635 898 LOC100996664 899 LOC101805491 900 LOC101926943 901LOC101927045 902 LOC101927142 903 LOC101927196 904 LOC101927314 905LOC101927391 906 LOC101927437 907 LOC101927516 908 LOC101927550 909LOC101927560 910 LOC101927661 911 LOC101927708 912 LOC101927919 913LOC101927972 914 LOC101928131 915 LOC101928134 916 LOC101928140 917LOC101928143 918 LOC101928253 919 LOC101928307 920 LOC101928336 921LOC101928370 922 LOC101928429 923 LOC101928443 924 LOC101928495 925LOC101928517 926 LOC101928530 927 LOC101928535 928 LOC101928622 929LOC101928797 930 LOC101928847 931 LOC101928858 932 LOC101928936 933LOC101928940 934 LOC101929353 935 LOC101929372 936 LOC101929517 937LOC101929529 938 LOC101929541 939 LOC101929577 940 LOC101929586 941LOC101929633 942 LOC101929662 943 LOC101929709 944 LOC101929753 945LOC101930085 946 LOC102467217 947 LOC102723313 948 LOC102723335 949LOC102723373 950 LOC102723439 951 LOC102723544 952 LOC102723833 953LOC102724153 954 LOC102724264 955 LOC102724297 956 LOC102724601 957LOC102725080 958 LOC105372795 959 LOC105373352 960 LOC105373876 961LOC105376365 962 LOC105377342 963 LOC105377651 964 LOC105377967 965LOC105378098 966 LOC105378146 967 LOC105378330 968 LOC105378385 969LOC105378853 970 LOC106699570 971 LOC148709 972 LOC283177 973 LOC283387974 LOC283683 975 LOC284581 976 LOC286059 977 LOC339529 978 LOC339666979 LOC392364 980 LOC399716 981 LOC400655 982 LOC401127 983 LOC401442984 LOC403312 985 LOC439933 986 LOC440311 987 LOC574538 988 LOC643201989 LOC643406 990 LOC643733 991 LOC645513 992 LOC645752 993 LOC646762994 LOC728158 995 LOC728327 996 LOC728392 997 LOC729224 998 LOC729603999 LOC729870 1000 LOC730202 1001 LOC730234 1002 LOC91548 1003 LOXL31004 LPAR5 1005 LPAR6 1006 LPP-AS2 1007 LRFN1 1008 LRIT2 1009 LRP8 1010LRRC32 1011 LRRC57 1012 LRRC58 1013 LRRC61 1014 LRRC66 1015 LRRC75A 1016LRRIQ1 1017 LRRIQ4 1018 LSAMP-AS1 1019 LSM14B 1020 LSMEM1 1021 LUC7L1022 LURAP1 1023 LUZP4 1024 LYPD5 1025 LYRM9 1026 LYVE1 1027 MAGEA111028 MAGEA8 1029 MAGEA8-AS1 1030 MAGEB6 1031 MAGEE2 1032 MAGEL2 1033MAGIX 1034 MAGOH2P 1035 MALSU1 1036 MAN1C1 1037 MAP1A 1038 MAP2K4P1 1039MAP3K21 1040 MAP3K8 1041 MAPRE1 1042 MAPT 1043 MAPT-IT1 1044 MASP1 1045MATN3 1046 MBL2 1047 MBLAC2 1048 MCCC1 1049 MCF2L 1050 MCM6 1051MCPH1-AS1 1052 MCRS1 1053 MDM2 1054 MEAT6 1055 MED13 1056 MED20 1057MED28 1058 MED8 1059 MEDAG 1060 METTL11B 1061 METTL25 1062 MFAP4 1063MFGE8 1064 MFN2 1065 MGAT4D 1066 MGC15885 1067 MGC16275 1068 MGC347961069 MGEA5 1070 MGME1 1071 MGST3 1072 MICALCL 1073 MICU2 1074 MICU3 1075MIER2 1076 MINDY1 1077 MIR1243 1078 MIR1298 1079 MIR1343 1080 MIR23C1081 MIR2681 1082 MIR302D 1083 MIR3121 1084 MIR3146 1085 MIR4306 1086MIR4439 1087 MIR4447 1088 MIR4464 1089 MIR4501 1090 MIR548F3 1091MIR548X 1092 MIR562 1093 MIR5689HG 1094 MIR571 1095 MIR6130 1096 MIR6201097 MIR624 1098 MIR8062 1099 MKRN2 1100 MKX-AS1 1101 MLLT3 1102 MMAA1103 MMP1 1104 MMP12 1105 MNAT1 1106 MOB1B 1107 MORF4L1 1108 MORF4L21109 MORN1 1110 MPZ 1111 MRAS 1112 MRFAP1 1113 MRGPRX1 1114 MRGPRX3 1115MRPL17 1116 MRPL19 1117 MRPL30 1118 MRPL37 1119 MRPL45P2 1120 MRPL521121 MRPL9 1122 MRPS18C 1123 MRPS22 1124 MRS2P2 1125 MS4A14 1126 MS4A4E1127 MSANTD4 1128 MSC-AS1 1129 MSH6 1130 MSL3 1131 MSL3P1 1132 MSRB21133 MTERF2 1134 MTRNR2L3 1135 MTRNR2L4 1136 MTRNR2L5 1137 MTX3 1138MUC21 1139 MUM1L1 1140 MUTYH 1141 MXD4 1142 MXRA5 1143 MYC 1144 MYF51145 MYH16 1146 MYL1 1147 MYLK2 1148 MYSM1 1149 NAA30 1150 NAA35 1151NAALAD2 1152 NAGA 1153 NANOS1 1154 NANP 1155 NAT1 1156 NAT16 1157NAV2-AS4 1158 NBPF13P 1159 NCALD 1160 NCAPD3 1161 NCAPG 1162 NCBP2L 1163NCK1-AS1 1164 NCKIPSD 1165 NCL 1166 NDST3 1167 NDUFA4 1168 NDUFB8 1169NDUFV2-AS1 1170 NECTIN3-AS1 1171 NEDD9 1172 NEFM 1173 NEGR1-IT1 1174NEK8 1175 NELFCD 1176 NETO2 1177 NEUROD6 1178 NFAT5 1179 NFE2L3 1180NFIA-AS2 1181 NFIB 1182 NFIC 1183 NHLH1 1184 NHLRC3 1185 NIFK 1186NIPBL-AS1 1187 NIPSNAP3A 1188 NIPSNAP3B 1189 NKAIN3 1190 NKAPL 1191 NKRF1192 NKX1-2 1193 NLGN2 1194 NLRP2B 1195 NLRP7 1196 NNT-AS1 1197 NOL31198 NOS2 1199 NOV 1200 NPTN 1201 NPVF 1202 NR2F1-AS1 1203 NRG3-AS1 1204NRIP2 1205 NRN1 1206 NSMCE3 1207 NT5E 1208 NTM-AS1 1209 NTS 1210 NUBP11211 NUDT5 1212 NUFIP1 1213 NUGGC 1214 NUF188 1215 NXF4 1216 NXFE3 1217OCLM 1218 ODAM 1219 ODF4 1220 OGT 1221 OLFM5P 1222 OLMALINC 1223 OMG1224 OR10A7 1225 OR10AD1 1226 OR10AG1 1227 OR10H2 1228 OR10Q1 1229OR10R2 1230 OR10S1 1231 OR10T2 1232 OR11H6 1233 OR11H7 1234 OR12D2 1235OR14J1 1236 OR1A2 1237 OR1E3 1238 OR1F2P 1239 OR1J1 1240 OR1K1 1241OR1S1 1242 OR2A25 1243 OR2AG1 1244 OR2AG2 1245 OR2AJ1 1246 OR2C3 1247OR2D2 1248 OR2F1 1249 OR2M1P 1250 OR2T27 1251 OR2T7 1252 OR2V1 1253OR2V2 1254 OR2W5 1255 OR4C12 1256 OR4C13 1257 OR4C3 1258 OR4E2 1259OR4F6 1260 OR4K13 1261 OR4Q2 1262 OR4S1 1263 OR51E1 1264 OR51I2 1265OR51T1 1266 OR52B6 1267 OR52E2 1268 OR52E4 1269 OR52N2 1270 OR52N5 1271OR52W1 1272 OR52Z1 1273 OR5AC2 1274 OR5B3 1275 OR5K3 1276 OR5M8 1277OR6B1 1278 OR6C2 1279 OR6C68 1280 OR6C74 1281 OR6K3 1282 OR6S1 1283OR7A5 1284 OR7C1 1285 OR7C2 1286 OR7D2 1287 OR7E24 1288 OR7G1 1289 OR8A11290 OR8B4 1291 OR8J3 1292 OR9A4 1293 OSTF1 1294 OSTM1 1295 OTOR 1296OTUB2 1297 OTUD1 1298 OTUD6B-AS1 1299 OVAAL 1300 PABPC5-AS1 1301PACRG-AS1 1302 PACS1 1303 PACSIN2 1304 PADI2 1305 PAFAH2 1306 PAGE2 1307PAK1IP1 1308 PAPD7 1309 PAPSS2 1310 PARP3 1311 PARP8 1312 PATE3 1313PAWR 1314 PAX2 1315 PAX6 1316 PAXBP1-AS1 1317 PBDC1 1318 PBX1 1319PCDH9-AS3 1320 PCDHA11 1321 PCDHA13 1322 PCDHA2 1323 PCDHA5 1324 PCDHAC11325 PCDHAC2 1326 PCDHB1 1327 PCDHB12 1328 PCDHB15 1329 PCDHB16 1330PCDHB4 1331 PCDHB8 1332 PCDHGA12 1333 PCDHGA2 1334 PCDHGA5 1335 PCDHGA81336 PCDHGA9 1337 PCDHGB4 1338 PCDHGB5 1339 PCDHGB6 1340 PCDHGB8P 1341PCDHGC4 1342 PCDHGC5 1343 PCGF3 1344 PCK2 1345 PCMTD1 1346 PCOTH 1347PCTP 1348 PDAP1 1349 PDC 1350 PDE6D 1351 PDK4 1352 PDLIM1 1353 PDPK11354 PDZD8 1355 PECR 1356 PELO 1357 PEX2 1358 PEX5 1359 PFDN4 1360PFKFB1 1361 PFN4 1362 PGBD2 1363 PGK1 1364 PGLYRP1 1365 PGM2L1 1366PGM5P2 1367 PGR-AS1 1368 PGRMC2 1369 PHC1 1370 PHF20L1 1371 PHF24 1372PHLDA3 1373 PHYHD1 1374 PI4K2B 1375 PIGBOS1 1376 PIGZ 1377 PIN1P1 1378PIN4P1 1379 PISRT1 1380 PITRM1 1381 PITRM1-AS1 1382 PITX2 1383 PKD2L11384 PLA2G4F 1385 PLAGL1 1386 PLCL2 1387 PLEKHA1 1388 PLEKHA4 1389PLEKHB2 1390 PLIN1 1391 PLPP1 1392 PLPP3 1393 PLPPR1 1394 PLPPR2 1395PLRG1 1396 PLSCR2 1397 PLUT 1398 PMCH 1399 PMS2P1 1400 PNLIPRP3 1401PNMA8B 1402 PNRC2 1403 POLG2 1404 POLN 1405 POM121L12 1406 POM121L2 1407POMP 1408 POPDC3 1409 POU2F3 1410 PPARG 1411 PPBPP2 1412 PPIE 1413 PPM1E1414 PPM1F 1415 PPM1N 1416 PPP1R10 1417 PPP1R14D 1418 PPP1R15A 1419PPP1R7 1420 PPP1R9B 1421 PPP4R3C 1422 PPWD1 1423 PRDM13 1424 PRKAB1 1425PRKAR2A-AS1 1426 PRKX-AS1 1427 PRLHR 1428 PRMT6 1429 PRMT9 1430 PROK21431 PROKR2 1432 PROSER1 1433 PRPF38A 1434 PRPS1 1435 PRR15L 1436 PRR23B1437 PRR23C 1438 PRR26 1439 PRRG4 1440 PRRT4 1441 PRSS22 1442 PRSS30P1443 PRSS46P 1444 PSD2-AS1 1445 PSG3 1446 PSG8 1447 PSMA3 1448 PSMC21449 PSMD10 1450 PSMD12 1451 PSMD9 1452 PSTK 1453 PTAFR 1454 PTBP3 1455PTGDR 1456 PTPN2 1457 PTPRA 1458 PTPRG-AS1 1459 PTTG1 1460 PURG 1461PUS3 1462 PXN 1463 PYCARD-AS1 1464 QKI 1465 RAB23 1466 RABIF 1467 RAD511468 RAD51AP1 1469 RAET1G 1470 RAG1 1471 RAP1B 1472 RAPGEF3 1473 RASL11B1474 RASSF10 1475 RASSF4 1476 RASSF6 1477 RBM11 1478 RBM15B 1479RBM26-AS1 1480 RBM3 1481 RBM44 1482 RBM46 1483 RBM48 1484 RBMS3-AS3 1485RBMX 1486 RBMXL2 1487 RBPJL 1488 RC3H2 1489 RCAN1 1490 REG1CP 1491 RERG1492 RFC3 1493 RFESD 1494 RFPL1 1495 RFPL1S 1496 RGR 1497 RGS12 1498RGS13 1499 RGS18 1500 RHOBTB1 1501 RHOJ 1502 RHOU 1503 RIF1 1504 RIOK21505 RLIM 1506 RLN2 1507 RNASE11 1508 RNASE2 1509 RNASE3 1510 RNASE41511 RNASE7 1512 RNF103 1513 RNF135 1514 RNF152 1515 RNF157-AS1 1516RNF167 1517 RNF168 1518 RNF24 1519 RNF31 1520 RNF34 1521 RNF39 1522 RNF51523 RPAP1 1524 RPL13AP17 1525 RPL22L1 1526 RPL31 1527 RPL6 1528 RPS201529 RPS3A 1530 RPTN 1531 RRM1 1532 RRP15 1533 RRP1B 1534 RRP8 1535 RRP91536 RRS1-AS1 1537 RSPH6A 1538 RTCA-AS1 1539 RTL9 1540 RUNX1-IT1 1541S1PR3 1542 SALL1 1543 SALL4 1544 SALRNA2 1545 SAMD9L 1546 SAP30 1547SASS6 1548 SATB2-AS1 1549 SCAF8 1550 SCARF1 1551 SCART1 1552 SCG2 1553SCGB1B2P 1554 SCGB1D1 1555 SCGB1D2 1556 SCGB1D4 1557 SCGB2B2 1558SCGB3A2 1559 SCML1 1560 SCO1 1561 SCUBE3 1562 SCYL3 1563 SDR39U1 1564SDR9C7 1565 SECISBP2 1566 SELENOP 1557 SELPLG 1568 SEMA4A 1569SEPSECS-AS1 1570 SERBP1 1571 SERPINA7 1572 SERPINB4 1573 SERTAD3 1574SERTM2 1575 SETD1B 1576 SGCD 1577 SGO2 1578 SH2D3C 1579 SH2D5 1580SH3D21 1581 SH3GLB1 1582 SHANK3 1583 SHB 1584 SHCBP1 1585 SHISA7 1586SHISAL2A 1587 SHOC2 1588 SHOX2 1589 SIAH1 1590 SIKE1 1591 SIRPA 1592SLAIN2 1593 SLC10A5 1594 SLC11A2 1595 SLC12A4 1596 SLC16A10 1597SLC16A12 1598 SLC16A13 1599 SLC16A9 1600 SLC17A2 1601 SLC22A10 1602SLC22A3 1603 SLC22A4 1604 SLC22A7 1605 SLC22A8 1606 SLC23A1 1607SLC25A16 1608 SLC25A19 1609 SLC25A32 1610 SLC25A35 1611 SLC25A36 1612SLC25A4 1613 SLC25A42 1614 SLC30A7 1615 SLC30A8 1616 SLC31A1 1617SLC35B4 1618 SLC35E4 1619 SLC35G1 1620 SLC35G3 1621 SLC36A1 1622 SLC37A21623 SLC37A3 1624 SLC46A1 1625 SLC51A 1626 SLC52A3 1627 SLC5A10 1628SLC5A3 1629 SLC5A6 1630 SLC5A8 1631 SLC6A11 1632 SLC6A4 1633 SLC6A7 1634SLC7A6OS 1635 SLC7A9 1636 SLC8B1 1637 SLFNL1 1638 SLITRK5 1639 SMAD1-AS21640 SMAD5-AS1 1641 SMIM10L2B 1642 SMIM12 1643 SMIM18 1644 SMIM27 1645SMLR1 1646 SMO 1647 SNAI2 1648 SNAPC5 1649 SNAR-I 1650 SNHG6 1651 SNIP11652 SNORA20B 1653 SNORA32 1654 SNORA8 1655 SNORA80A 1656 SNORA87 1657SNORD114-29 1658 SNORD114-30 1659 SNORD115-45 1660 SNORD38D 1661 SNORD3G1662 SNORD89 1663 SNORD91B 1664 SNRNP27 1665 SNX10 1666 SNX18 1667 SNX211668 SOST 1669 SOWAHB 1670 SOWAHC 1671 SP1 1672 SP2 1673 SPACA1 1674SPACA3 1675 SPATA3-AS1 1676 SPATA31D1 1677 SPATA31E1 1678 SPATA33 1679SPATA41 1680 SPC25 1681 SPEN 1682 SPINK7 1683 SPINK9 1684 SPINT4 1685SPRR1A 1686 SPRR2E 1687 SPRY2 1688 SPRYD4 1689 SRP14-AS1 1690 SRR 1691SRSF4 1692 SRSF7 1693 SSFA2 1694 SSR1 1695 SSR3 1696 SSX9 1697 ST13P41698 ST8SIA6 1699 STARD5 1700 STEAP4 1701 STK4-AS1 1702 STN1 1703 STOM1704 STON1 1705 STPG1 1706 STX16 1707 STX1B 1708 STXBP3 1709 STYK1 1710SUGT1 1711 SUMF1 1712 SUMO1P3 1713 SUPT20HL2 1714 SUPT3H 1715 SURF4 1716SUV39H1 1717 SVBP 1718 SYCE1L 1719 SYDE2 1720 SYNE1-AS1 1721 SYPL1 1722SYT4 1723 TAAR9 1724 TAB2-AS1 1725 TACSTD2 1726 TAF1L 1727 TAS1R1 1728TAS2R1 1729 TAS2R3 1730 TAS2R30 1731 TAS2R39 1732 TAS2R42 1733 TATDN21734 TBPL1 1735 TBR1 1736 TCAM1P 1737 TCEAL3 1738 TCEAL4 1739 TCEANC1740 TCF24 1741 TCHH 1742 TCHHL1 1743 TCOF1 1744 TCP11L1 1745 TCP11L21746 TDRD6 1747 TDRKH-AS1 1748 TEAD3 1749 TEAD4 1750 TEFM 1751 TET2 1752TEX101 1753 TFB2M 1754 TFE3 1755 TFF2 1756 TGFA 1757 TGFB3 1758 THAP21759 THEM4 1760 TIGD4 1761 TIMM21 1762 TIMM8A 1763 TIMM9 1764 TKTL2 1765TLCD2 1766 TLE3 1767 TLR1 1768 TLR4 1769 TLX1NB 1770 TM6SF1 1771 TMCO11772 TMEM128 1773 TMEM132E 1774 TMEM14EP 1775 TMEM155 1776 TMEM169 1777TMEM170A 1778 TMEM177 1779 TMEM200C 1780 TMEM209 1781 TMEM220 1782TMEM225 1783 TMEM229B 1784 TMEM235 1785 TMEM254 1786 TMEM255B 1787TMEM53 1788 TMEM62 1789 TMEM65 1790 TMEM81 1791 TMEM86A 1792 TMEM9 1793TMEM99 1794 TMIGD3 1795 TMOD4 1796 TMPPE 1797 TMPRSS4 1798 TMSB15A 1799TNFSF13B 1800 TNK2-AS1 1801 TNPO1 1802 TNRC17 1803 TNRC6C 1804 TOMM341805 TOP1P2 1806 TOPORS 1807 TP53 1808 TPCN2 1809 TPD52L3 1810 TPI1P21811 TPRG1-AS1 1812 TRAF6 1813 TRAM1 1814 TRAM1L1 1815 TRDN-AS1 1816TRIB1 1817 TRIB2 1818 TRIM23 1819 TRIM3 1820 TRIM32 1821 TRIM51 1822TRIM58 1823 TRIM69 1824 TRIQK 1825 TRMT5 1826 TRNT1 1827 TRPC7-AS2 1828TSC22D1 1829 TSGA13 1830 TSHR 1831 TSPAN2 1832 TSPYL4 1833 TSR1 1834TSSK1B 1835 TSSK4 1836 TTBK1 1837 TTC8 1838 TTF1 1839 TTL 1840 TTPA 1841TUBB4A 1842 TUBG1 1843 TWF1 1844 TXNDC2 1845 TYMS 1846 TYMSOS 1847 UBA51848 UBA6 1849 UBA7 1850 UBE2D1 1851 UBE2G1 1852 UBE2L6 1853 UBE2MP11854 UBE2N 1855 UBE2Q2 1856 UBR7 1857 UCA1 1858 UGDH 1859 UGT1A1 1860UGT1A10 1861 UNC45B 1862 UOX 1863 UPF1 1864 UPF3B 1865 USP15 1866 USP201867 USP30 1868 USP40 1869 USP51 1870 UTP14C 1871 UTP3 1872 VARS 1873VCAM1 1874 VGLL1 1875 VMA21 1876 VPS37C 1877 VPS51 1878 VPS53 1879 VSIG11880 VSIG10L 1881 VSTM2L 1882 VSTM5 1883 VSX1 1884 VWA5B2 1885 VWC2 1886WASF3 1887 WBP11 1888 WDFY4 1889 WDR45 1890 WDR55 1891 WDR92 1892 WFDC21893 WFDC5 1894 WFIKKN2 1895 WISP3 1896 WNT10B 1897 WNT9B 1898 WSB2 1899WTAP 1900 XCR1 1901 XK 1902 XKR4 1903 XKR6 1904 XKR9 1905 XXYLT1-AS21906 XYLT2 1907 YBEY 1908 YBX1 1909 YBX3P1 1910 YES1 1911 YIPF4 1912YIPF7 1913 YTHDF1 1914 ZBED2 1915 ZBED3 1916 ZBED6CL 1917 ZBTB24 1918ZBTB41 1919 ZBTB8B 1920 ZC2HC1A 1921 ZC3H15 1922 ZC3HAV1L 1923 ZCCHC101924 ZCCHC12 1925 ZDHHC2 1926 ZDHHC9 1927 ZFAND2B 1928 ZFP14 1929 ZFP911930 ZNF155 1931 ZNF19 1932 ZNF195 1933 ZNF207 1934 ZNF211 1935 ZNF2341936 ZNF235 1937 ZNF254 1938 ZNF260 1939 ZNF275 1940 ZNF280A 1941ZNF280C 1942 ZNF284 1943 ZNF30-AS1 1944 ZNF33BP1 1945 ZNF34 1946 ZNF3621947 ZNF384 1948 ZNF398 1949 ZNF432 1950 ZNF44 1951 ZNF460-AS1 1952ZNF503 1953 ZNF529-AS1 1954 ZNF559 1955 ZNF57 1956 ZNF571 1957 ZNF5771958 ZNF595 1959 ZNF611 1960 ZNF619 1961 ZNF665 1962 ZNF691 1963 ZNF6921964 ZNF70 1965 ZNF710 1966 ZNF770 1967 ZNF804A 1968 ZNF804B 1969 ZNF8051970 ZNF823 1971 ZNF843 1972 ZNF847P 1973 ZNF850 1974 ZRANB1 1975 ZSCAN21976 ZSCAN20 1977 ZSWIM9 1978 ZXDA 1979 ZYG11A 1980 AAMP 1981 ABCC5-AS11982 ADGRE5 1983 ADH1A 1984 AJAP1 1985 ALAD 1986 ALG1 1987 ALG14 1988ANKRD39 1989 APOA5 1990 AQP3 1991 ARHGEF25 1992 ARID5B 1993 ARL4D 1994ATE1-AS1 1995 ATP10B 1996 ATXN7L1 1997 B3GNT2 1998 B9D2 1999 BLK 2000BRD9 2001 BRINP2 2002 BYSL 2003 C12orf43 2004 C12orf50 2005 C12orf772006 C14orf144 2007 C16orf90 2008 C22orf24 2009 C4orf3 2010 C8orf74 2011CADM2-AS2 2012 CCAR1 2013 CCDC9 2014 CD2 2015 CD68 2016 CD82 2017 CD8A2018 CEACAM19 2019 CFB 2020 CHCHD5 2021 CHRNB2 2022 CIDECP 2023 CIT 2024CLDN11 2025 CMTM7 2026 CNGB1 2027 CNPPD1 2028 COL9A3 2029 CPA2 2030 CSTA2031 CWC25 2032 DDX47 2033 DEFB115 2034 DGKK 2035 DIAPH2-AS1 2036DISC1-IT1 2037 DNAH17-AS1 2038 DNAJC12 2039 DPH3P1 2040 DPRX 2041DPYD-AS1 2042 DYNC1I2 2043 EEF1AKMT2 2044 EIF2B2 2045 EIF4E2 2046 F32047 FADS2 2048 FAM214B 2049 FBXO9 2050 FBXW4 2051 FCF1P2 2052 FRG1DP2053 FRY-AS1 2054 FXYD5 2055 GABARAPL1 2056 GDF11 2057 GGA3 2058 GID42059 GNG7 2060 GPATCH1 2061 GPATCH4 2062 GPC6 2063 GPR153 2064 GPX3 2065GRAMD2A 2066 GRB10 2067 GRM7 2068 HAX1 2069 HMGB1 2070 HNRNPH1 2071HSD17B2 2072 IDH3B 2073 INO80D 2074 INTS14 2075 IVD 2076 JAKMIP1 2077KANSL1-AS1 2078 KATNAL1 2079 KCNA4 2080 KCNK10 2081 KCTD2 2082 KDM4D2083 KLHL29 2084 KRBOX4 2085 KRT18 2086 LAIR1 2087 LHFPL3-AS1 2088 LIN92089 LINC00114 2090 LINC00342 2091 LINC00347 2092 LINC00433 2093LINC00443 2094 LINC00536 2095 LINC00599 2096 LINC00694 2097 LINC007042098 LINC00705 2099 LINC00864 2100 LINC01005 2101 LINC01048 2102LINC01102 2103 LINC01118 2104 LINC01220 2105 LINC01231 2106 LINC013072107 LINC01354 2108 LINC01470 2109 LINC01482 2110 LINC01555 2111LINC01611 2112 LINC01750 2113 LINC01910 2114 LINC01930 2115 LINC021182116 LINC02214 2117 LINC02219 2118 LINC02274 2119 LINC02280 2120LINC02351 2121 LOC100653233 2122 LOC101926933 2123 LOC101927278 2124LOC101927365 2125 LOC101927822 2126 LOC101928087 2127 LOC101928445 2128LOC101929124 2129 LOC102725126 2130 LOC105370473 2131 LOC105375843 2132LOC105376351 2133 LOC339685 2134 LOC399886 2135 LOC401176 2136 LSP1P32137 LIB4R 2138 MAEL 2139 MAGEB5 2140 MAN2B1 2141 MAP6 2142 MARF1 2143MCHR2-AS1 2144 MED13L 2145 METTL5 2146 MGAT1 2147 MIATNB 2148 MIR13052149 MIR205HG 2150 MIR3936 2151 MIR3937 2152 MIR4423 2153 MIR4477A 2154MIR548BA 2155 MIR576 2156 MIR585 2157 MIR6082 2158 MIR8074 2159 MIR80762160 MIXL1 2161 MLX 2162 MOBP 2163 MPV17L 2164 MRPS10 2165 MRPS11 2166MSH2 2167 MYBPHL 2168 MYZAP 2169 NAA10 2170 NECAB2 2171 NEDD1 2172 NELFE2173 NEU2 2174 NFKB1 2175 NIPAL2 2176 NNMT 2177 NPL 2178 NREP 2179 NTRK32180 ODC1 2181 OOEP 2182 OR4B1 2183 OR4C11 2184 OSER1-AS1 2185 OVCH22186 PCAT19 2187 PCDH9-AS4 2188 PCP4L1 2189 PHOSPHO1 2190 PIGL 2191 PIGW2192 PIP5K1C 2193 PLA2G10 2194 PMS2 2195 POLR2J4 2196 PPM1D 2197 PPP2R2B2198 PPP2R2C 2199 PSG5 2200 PSMA6 2201 PTEN 2202 RALGDS 2203 RASSF5 2204RBFADN 2205 RBM15 2206 RET 2207 RGS10 2208 RIMBP2 2209 RMST 2210 RNF2072211 RNR1 2212 RNR2 2213 RUBCNL 2214 RXFP2 2215 RYR3 2216 S100A2 2217SAMD7 2218 SCARNA3 2219 SEMA4F 2220 SERP2 2221 SERPINB11 2222 SFMBT22223 SFPQ 2224 SHISA6 2225 SIM1 2226 SIRT5 2227 SKIV2L 2228 SLAMF8 2229SLC17A4 2230 SLC22A5 2231 SLC23A3 2232 SLC5A4 2233 SLC6A16 2234SMIM15-AS1 2235 SMUG1 2236 SNORD114-14 2237 SNORD114-15 2238 SNORD114-192239 SPACA6P-AS 2240 SPANXN5 2241 SPIRE2 2242 SRRM1 2243 STK3 2244 STK352245 STT3B 2246 STX4 2247 SYAP1 2248 SYT17 2249 TARDBP 2250 TAS2R16 2251TBC1D26 2252 TBL2 2253 TCFL5 2254 THRA 2255 THY1 2256 TLR8 2257 TMBIM12258 TMCC1 2259 TMEM139 2260 TMEM42 2261 TMEM5-AS1 2262 TMEM98 2263TNFRSF1A 2264 TOX4 2265 TRNP1 2266 TTC32 2267 TXN2 2268 TXNL4A 2269 TYR2270 UBE4B 2271 UBXN10-AS1 2272 UGT2A1 2273 UTP4 2274 VIM 2275 VTRNA1-12276 VWC2L 2277 WDR11-AS1 2278 WDR61 2279 WDR91 2280 WLS 2281 YEATS22282 YEATS2-AS1 2283 ZC3H12C 2284 ZDHHC11B 2285 ZFP2 2286 ZMYND10 2287ZNF14 2288 ZNF142 2289 ZNF157 2290 ZNF160 2291 ZNF182 2292 ZNF230 2293ZNF346 2294 ZNF441 2295 ZNF462 2296 ZNF534 2297 ZNF544 2298 ZNF56 2299ZNF569 2300 ZNF613 2301 ZNF627 2302 ZNF684 2303 ZNF707 2304 ZNF883 2305ZNF98 2306 ZRSR2

Example 7: Construction of a Classifier for Typing Cervical CancerPatients Using Erythrocyte Micronuclei DNA

In this example, there were 8 subjects, including 2 patients diagnosedas cervical adenocarcinoma and 5 patients diagnosed as cervical squamouscell carcinoma by other methods.

The peripheral blood samples from patients with cervical cancer wereexpressed in the form of “P” plus patient number. For example, “P1”represents a peripheral blood sample from the first cervical cancerpatient (“Patient 1”), “P2” represents a peripheral blood sample fromthe second cervical cancer patient (“Patient 2”), and so on.

The basic information of 7 patients with cervical cancer is shown inTable 3. “Cervical cancer type” refers to the type of cervical cancerdiagnosed by other methods.

TABLE 3 HPV Maximum Patient Detected diameter of Existence of lymphnumber Age value tumor (cm) Type of cervical cancer node metastasis ornot 1 44 68.36 2.1 Medium-high differentiated No adenocarcinoma 2 3650.13 4.2 Low-medium differentiated No adenocarcinoma 3 71 1212.8 2.6Medium differentiated Yes (without surgery) squamous cell carcinoma 4 43240.09 4.1 Low differentiated Yes (without surgery) squamous cellcarcinoma 5 65 25.55 3.3 Medium differentiated No squamous cellcarcinoma 6 56 503.61 3.2 Low-medium differentiated No squamous cellcarcinoma  7* 37 No 5.4 Low-medium differentiated Yes squamous cellcarcinoma *Patient 7 is an HPV negative patient.

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Specifically, 2 adenocarcinoma samples and 6 squamous cell carcinoma(including one HPV-negative sample) in primary cervical cancer sampleswere selected for the reads counting, and 360 differential genes werescreened out by ANOVA test to distinguish the two classes of samples.Then, according to Pearson correlation, the two classes of samples wereclustered in unsupervised hierarchy, showing that there were significantdifferences between the two classes of samples.

As shown in FIG. 6 , 360 differential genes (forming a classifier fordistinguishing cervical adenocarcinoma from cervical squamous cellcarcinoma patients) were clustered. In FIG. 6 , each row represents adifferential gene, and each column represents a patient.

The list of 360 differential genes is shown in Table 4. Each genecorresponds to each row from top to bottom in FIG. 6 .

TABLE 4 1 ACAD10 2 ACOD1 3 ACTR1A 4 ANP32A-IT1 5 ARL5C 6 ATP13A2 7 B2M 8C11orf70 9 C16orf70 10 C19orf66 11 C1orf194 12 CABYR 13 CADM2-AS2 14CALB1 15 CAPSL 16 CCT8 17 CNFN 18 CROCC 19 CYP27C1 20 DNAAF1 21 DYNLRB222 ESCO1 23 ESYT3 24 FAM199X 25 FAM19A1 26 FGFBP3 27 FITM2 28 FLJ3720129 GLA 30 GPN1 31 GTF2H1 32 HAS2-AS1 33 HOXD1 34 IP6K3 35 KCNH3 36KRTAP22-2 37 LINC00605 38 LINC01393 39 LINC01602 40 LINC01803 41LINC01845 42 LINC01991 43 LOC101928211 44 LOC101929130 45 LOC10192952446 LOC102467081 47 LOC107133515 48 LRRC17 49 LUC7L2 50 LYPLA1 51 MARCH452 MGAT4EP 53 MINDY4B 54 MIR3663HG 55 MIR553 56 MKRN3 57 MRPS18C 58NBPF9 59 NDUFV2 60 NKRF 61 NUDT5 62 OMA1 63 OR10J1 64 OR10Z1 65 OR1S1 66OR4C11 67 OR4X1 68 OR51B5 69 OR5AN1 70 P4HA1 71 PCED1B 72 SLC22A7 73SLC35B2 74 SLC35F3 75 SMS 76 SNORD3K 77 SVIP 78 TAF6 79 TAS2R3 80 TCAM1P81 TGM1 82 TGOLN2 83 TMCO2 84 TMEM132A 85 TMEM14EP 86 TREML4 87 TSPAN3188 UBE2N 89 VAMP4 90 XIAP 91 ZNF718 92 ADAM30 93 AMER3 94ANKRD62P1-PARP4P3 95 ANP32A 96 APOF 97 APOOP5 98 ARHGEF25 99 ASAP1-IT2100 ASF1B 101 ASIC2 102 ASNS 103 ATP6V0B 104 BANCR 105 BMS1P21 106BOD1L2 107 BRWD1-AS2 108 BTNL8 109 C12orf71 110 C2orf88 111 C6orf222 112C9orf3 113 CAHM 114 CD24 115 CDKN2AIP 116 CEP170 117 CERS3 118 CFL2 119CHAMP1 120 CHERP 121 CHRNE 122 CLLU1 123 CNOT8 124 COL23A1 125 COL4A1126 CREB3L3 127 CTAGE9 128 CTRC 129 CYB5R1 130 CYMP-AS1 131 CYP4F29P 132DCAF8L1 133 DCK 134 DEFA11P 135 DGCR11 136 DGCR9 137 DICER1-AS1 138DLGAP3 139 DPPA3 140 DPY19L1P2 141 DSCR9 142 EDAR 143 EIF3IP1 144 EIF5A145 ESRP2 146 FABP3 147 FAM129A 148 FAM49A 149 FBXL19-AS1 150 FFAR2 151FKBP1A 152 FRMD1 153 GABPB1-AS1 154 GAGE1 155 GALNT16 156 GCK 157 GNAI3158 GPR83 159 GRIK1-AS1 160 GSX1 161 GTF2H5 162 GTPBP2 163 H19 164HLA-DQB1 165 HOXC4 166 HRAT5 167 HSD17B1 168 IFITM10 169 IFNA1 170 IGLL1171 INSL4 172 KAZN-AS1 173 KCNG1 174 KCNIP3 175 KCNJ9 176 KCNQ4 177KIRREL2 178 KLF4 179 KRTAP20-2 180 LAMB2P1 181 LCE1E 182 LINC00312 183LINC00449 184 LINC00469 185 LINC00547 186 LINC00561 187 LINC00656 188LINC00680 189 LINC00851 190 LINC00857 191 LINC00887 192 LINC01058 193LINC01118 194 LINC01496 195 LINC01565 196 LINC01579 197 LINC01621 198LINC01658 199 LINC01674 200 LINC01737 201 LINC01752 202 LINC01833 203LINC01872 204 LINC01894 205 LINC01953 206 LINC01964 207 LINC01982 208LINC02145 209 LINC02214 210 LINC02226 211 LINC02283 212 LINC02313 213LINC02468 214 LOC100129129 215 LOC100130872 216 LOC100190986 217LOC100505824 218 LOC100506585 219 LOC100996415 220 LOC101593348 221LOC101927342 222 LOC101927497 223 LOC101927588 224 LOC101927762 225LOC101928307 226 LOC101928489 227 LOC103611081 228 LOC105369632 229LOC105371880 230 LOC105372493 231 LOC105373876 232 LOC105377967 233LOC105378385 234 LOC105378663 235 LOC285556 236 LOC400682 237 LOC441666238 LOC643802 239 LOC646903 240 LOC729681 241 LRRC3-AS1 242 LRRC4B 243LY6K 244 LYZL2 245 MAGEB6 246 MECOM 247 MESTIT1 248 MGAT1 249 MIR205HG250 MIR30B 251 MIR4677 252 MIR502 253 MIR503HG 254 MIR513A1 255 MIR7852256 MIRLET7F2 257 MKLN1-AS 258 MN1 259 MRGPRX2 260 MRPL33 261 MT1IP 262MTCH1 263 MXRA5 264 NANOGP8 265 NCF4 266 NDRG4 267 NDST1-AS1 268 NDUFC2269 NECAP1 270 NEIL1 271 NKD1 272 NMNAT1 273 NUDT16 274 NUS1 275 OR13H1276 OR2B6 277 OR4K2 278 OR51D1 279 OR5M11 280 OTOF 281 OTUB2 282P3H2-AS1 283 PACERR 284 PADI4 285 PCDHGA12 286 PDLIM2 287 PGAM4 288PHGR1 289 PIGW 290 PIP5KL1 291 PLEC 292 PMCHL1 293 POLH 294 POU5F1 295PRAMEF12 296 PRAMEF2 297 PRSS16 298 PSG9 299 PSMA6 300 PTPN12 301 RBM15302 RGS1 303 RPUSD2 304 SALL3 305 SCG5 306 SELL 307 SERPINE1 308 SEZ6L2309 SHISA2 310 SIGLEC14 311 SLC25A21-AS1 312 SLC25A3P1 313 SLC39A1 314SLC5A2 315 SMAD5-AS1 316 SMARCD2 317 SNHG20 318 SNORA120 319 SNORA70I320 SNORD113-5 321 SOX4 322 SPATA19 323 SPON2 324 SPSB4 325 SSX8 326SUCLG1 327 SYNJ2BP 328 TARP 329 TAS2R14 330 TCEAL1 331 TIGIT 332 TMEM134333 TMEM14A 334 TMEM45B 335 TMEM80 336 TNK1 337 TRAPPC2 338 TRIM6 339TRIP13 340 TSTD3 341 TTPAL 342 TUBA3FP 343 TUSC8 344 UBE2E1 345 UBE2G2346 UBE2V2 347 UBXN1 348 UG0898H09 349 UPK3A 350 VAMP5 351 WDR83 352ZCCHC10 353 ZFHX4-AS1 354 ZFP57 355 ZFP69B 356 ZNF217 357 ZNF319 358ZNF76 359 ZNF792 360 ZWINT

Example 8: Construction of a Classifier for Staging Cervical CancerPatients Using Erythrocyte Micronuclei DNA

In this example, there were 5 subjects, including 2 patients diagnosedas medium differentiated cervical squamous cell carcinoma by othermethods and 3 patients diagnosed as low differentiated and low-mediumdifferentiated cervical squamous cell carcinoma.

The peripheral blood samples from patients with cervical cancer wereexpressed in the form of “P” plus patient number. For example, “P1”represents a peripheral blood sample from the first cervical cancerpatient (“Patient 1”), “P2” represents a peripheral blood sample fromthe second cervical cancer patient (“Patient 2”), and so on.

The basic information of 5 patients with cervical cancer is shown inTable 5. “Cervical cancer type” refers to the type of cervical cancerdiagnosed by other methods.

TABLE 5 HPV Maximum Patient Detected diameter of Existence of lymphnumber Age value tumor (cm) Type of cervical cancer node metastasis ornot 1′ 65 25.55 3.3 Medium differentiated No squamous cell carcinoma 2′71 1212.8 2.6 Medium differentiated Yes (without surgery) squamous cellcarcinoma 3′ 43 240.09 4.1 low differentiated Yes (without surgery)squamous cell carcinoma  4′* 37 No 5.4 Low-medium Yes differentiatedsquamous cell carcinoma 5′ 56 503.61 3.2 Low-medium No differentiatedsquamous cell carcinoma *Patient 4 was HPV negative.

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Specifically, 2 medium differentiated cervical squamous cell carcinomasamples and 3 low differentiated and low-medium differentiated squamouscell carcinoma samples in primary cervical squamous cell carcinomasamples were selected for the reads counting, and 466 differential geneswere screened out by ANOVA test to distinguish the two classes ofsamples. Then, according to Pearson correlation, the two classes ofsamples were clustered in unsupervised hierarchy, showing that therewere significant differences between the two classes of samples.

As shown in FIG. 7 , 466 differential genes (forming a classifier fordistinguishing medium differentiated cervical squamous cell carcinomafrom cervical low differentiated and low-medium differentiated squamouscell carcinoma patients) were clustered. In FIG. 7 , each row representsa differential gene, and each column represents a patient.

The list of 466 differential genes is shown in Table 6. Each genecorresponds to each row from top to bottom in FIG. 7 .

TABLE 6 1 ACP1 2 ADAD1 3 AGAP1-IT1 4 AKAP7 5 AKR7A2 6 ANKRD27 7 ANXA9 8ARMC12 9 ASCL4 10 AZIN1 11 B2M 12 BACE1 13 BANF2 14 C12orf74 15 C15orf4816 C15orf59-AS1 17 C18orf61 18 C19orf66 19 C21orf62 20 C2orf69 21C2orf81 22 C3orf56 23 C8orf34-AS1 24 C9orf66 25 CARD18 26 CASC11 27CASP14 28 CCR5 29 CDIP1 30 CDK9 31 CENPVL3 32 CERNA2 33 CFTR-AS1 34CIITA 35 CLEC2B 36 CLRN1-AS1 37 COA5 38 CPHXL 39 CPNE6 40 CPXCR1 41CRYBG3 42 CYP4V2 43 DBF4B 44 DBIL5P 45 DDX39B-AS1 46 DPYS 47 DUSP1 48EBNA1BP2 49 EDEM1 50 EEF1E1 51 ELOA2 52 EMC1 53 FAM111A-DT 54 FAM185A 55FAM201B 56 FAM219A 57 FAM237A 58 FAM24A 59 FAR2P2 60 FGFBP3 61 FLJ3600062 FLJ37201 63 FOXP1-AS1 64 FTSJ1 65 GASAL1 66 GKN2 67 GNG5 68 GOLM1 69GPR55 70 GSN-AS1 71 HACD4 72 HHEX 73 HIP1 74 HIST1H3H 75 HIST4H4 76HNRNPA1P10 77 HSPA1L 78 IKZF4 79 IL10RB-AS1 80 IL1R1 81 IL26 82 INAFM183 ITPK1 84 KAZN 85 KCNAB1-AS2 86 KDM4A-AS1 87 KDM8 88 KIAA1456 89 KLF1290 KLHL15 91 KRR1 92 KRT77 93 KRTAP16-1 94 KRTAP29-1 95 KRTAP6-1 96LGALS12 97 LHFPL6 98 LHX4-AS1 99 LINC00299 100 LINC00317 101 LINC00415102 LINC00485 103 LINC00563 104 LINC00676 105 LINC00919 106 LINC01114107 LINC01203 108 LINC01644 109 LINC01876 110 LINC02041 111 LINC02120112 LINC02210 113 LINC02308 114 LINC02310 115 LOC100128288 116LOC100131496 117 LOC100505635 118 LOC100505715 119 LOC101927402 120LOC101927523 121 LOC101927884 122 LOC101929718 123 LOC102723883 124LOC105370954 125 LOC105373064 126 LOC105377348 127 LOC105378052 128LOC643406 129 LOC646548 130 LOC727896 131 LPCAT3 132 LRRC17 133 LRRC42134 LY9 135 MAGEA11 136 MBIP 137 MCM3 138 MED28 139 METTL18 140 MIR1322141 MIR3663HG 142 MIR4303 143 MIR4699 144 MIR570HG 145 MLIP-AS1 146MORF4L1 147 MSANTD2 148 MYH2 149 MYO9B 150 MYOZ3 151 NAA30 152 NDNF 153NEU2 154 NFYC-AS1 155 NHS-AS1 156 NKILA 157 NKX3-1 158 NPTN-IT1 159NRG1-IT1 160 NRN1 161 NTM-IT 162 OR10Q1 163 OR10Z1 164 OR13C3 165 OR1Q1166 OR2K2 167 OR8K3 168 OR9G4 169 OTUD7B 170 OTX2 171 PCDHA10 172PCDHB14 173 PCDHGA1 174 PCDHGC4 175 PCDHGC5 176 PCED1B 177 PFAS 178PICART1 179 PLP1 180 PNISR 181 PRKAB2 182 PRKAR1A 183 PROKR2 184 PSMD3185 PSTK 186 PTTG2 187 QARS 188 RAB11FIP4 189 RAB31 190 RBMXL2 191RBPMS-AS1 192 RMDN3 193 RNF152 194 RPS17 195 RRAS 196 SAMD9L 197SCARNA17 198 SCARNA6 199 SCRT2 200 SET 201 SLC39A2 202 SLC3A2 203SLC9A9-AS1 204 SMARCA5-AS1 205 SNAP25-AS1 206 SNORD3K 207 SNRNP35 208SPATA7 209 SPRR4 210 SRGAP3-AS2 211 SYNPR-AS1 212 TBCEL 213 TENM4 214TEX53 215 TIGD2 216 TMEM140 217 TMEM214 218 TRIM3 219 TXNDC2 220 TXNL1221 TYW5 222 UBN1 223 UBQLN2 224 UCK2 225 UPP1 226 UQCRQ 227 VPS35 228VPS37A 229 VPS45 230 VTI1A 231 XAF1 232 XPC 233 ZBTB33 234 ZFP37 235ZMYM3 236 ZNF212 237 ZNF329 238 ZNF492 239 ZNF550 240 ZNF70 241 ZNF740242 ZNF770 243 ZNF827 244 ZPBP2 245 ZSCAN29 246 AARD 247 ABCB8 248ACOXL-AS1 249 ACTN1-AS1 250 ADAMTS2 251 AHSG 252 AP2A1 253 ARHGEF7-AS2254 ARMS2 255 BAALC-AS2 256 BMP4 257 BOLA1 258 C11orf42 259 C16orf52 260C17orf102 261 C17orf62 262 C19orf48 263 C19orf57 264 C5orf66-AS2 265C6orf120 266 CAPNS2 267 CASC17 268 CATIP-AS2 269 CCL3L1 270 CD274 271CDC42EP2 272 CDKN2A-AS1 273 CELSR3 274 CEP19 275 CEP85 276 CLLU1 277COX16 278 CSE1L 279 CSPG4 280 CSRP2 281 CSTA 282 DCP2 283 DCUN1D1 284DDIT4L 285 DDX21 286 DGCR9 287 DHH 288 DOHH 289 DPYD-AS2 290 DSCAM-AS1291 EAF1 292 EGFLAM-AS4 293 EHBP1L1 294 EPOR 295 FAM189B 296 FAM32A 297FAM43A 298 FAM90A27P 299 FBRS 300 FBXL15 301 FLNB-AS1 302 FOXD1 303FOXO4 304 FPR1 305 FPR2 306 FRY-AS1 307 FSCN3 308 GCSAM 309 GDF6 310GFRA4 311 GJB4 312 GPR179 313 GPRC5C 314 GPSM3 315 GRM7-AS1 316 GSG1L317 H3F3AP4 318 HCG4B 319 HCP5 320 HHATL 321 HIST1H2AB 322 HLA-DMB 323HLA-F 324 HLA-H 325 HNRNPUL2 326 HULC 327 HYAL4 328 IER2 329 IFIT5 330IGLL1 331 ING4 332 INTS5 333 IQCE 334 IRX6 335 KCNN1 336 KCNS2 337KIAA1147 338 KLHL11 339 KLK1 340 KRT7 341 LAMTOR5 342 LCE1E 343 LGI4 344LILRB1 345 LINC00174 346 LINC00459 347 LINC00513 348 LINC00526 349LINC00547 350 LINC00550 351 LINC00552 352 LINC00578 353 LINC01143 354LINC01204 355 LINC01502 356 LINC01732 357 LINC01782 358 LINC01833 359LINC01855 360 LINC01867 361 LINC01884 362 LINC01960 363 LINC02043 364LINC02441 365 LINC02530 366 LIPE-AS1 367 LMO1 368 LNX1-AS2 369LOC100128361 370 LOC100130476 371 LOC100131303 372 LOC100421746 373LOC100506178 374 LOC100507507 375 LOC101926963 376 LOC101927138 377LOC101927143 378 LOC101928177 379 LOC101928725 380 LOC101928791 381LOC101928887 382 LOC101929549 383 LOC101929721 384 LOC105371083 385LOC105373609 386 LOC105374952 387 LOC105377621 388 LOC105378397 389LOC105379393 390 LOC107984703 391 LOC148413 392 LOC257396 393 LOC387810394 LOC401320 395 LOC644936 396 LOC646903 397 LOC729224 398 LOC729305399 LRG1 400 LRP12 401 LSR 402 LUM 403 LUNAR1 404 MAGEB2 405 MAGEF1 406MAGIX 407 MALL 408 MAPK13 409 MAPKAPK5-AS1 410 MESP1 411 METTL3 412MGC4859 413 MIP 414 MIR1255A 415 MIR1265 416 MIR1291 417 MIR17HG 418MIR2682 419 MIR3145 420 MIR31HG 421 MIR4255 422 MIR548U 423 MIR5692C2424 MIR643 425 MIR7-3 426 MIR891B 427 MOB3A 428 MRAP 429 MRPL32 430MRPS30-DT 431 MSGN1 432 MUC22 433 NDUFAB1 434 NELFA 435 NHLRC1 436OLFML3 437 OR12D2 438 OR2AK2 439 OR2H1 440 OR51F1 441 OR51I2 442 OR5AP2443 OR6C65 444 OR6J1 445 OR6V1 446 OR8K1 447 OSCAR 448 OXA1L 449PAX6-AS1 450 PCDHA11 451 PLAC9 452 PLCH1-AS2 453 PLVAP 454 PPP1R3A 455PPP1R3D 456 PRC1-AS1 457 PRR15 458 PRR23C 459 PRRT2 460 PRSS41 461PRSS57 462 PTGS2 463 RAB6C-AS1 464 RAI2 465 RASGRP4 466 RBMXL3

Example 9. Classification of Healthy Individuals and Cervical CancerPatients Using Erythrocyte Micronuclei DNA

Using the classifier (2,306 genes) constructed in Example 6 forclustering healthy individuals and cervical cancer patients, 8 unknownsamples from 8 subjects were predicted.

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

After testing, it was found that 5 of the 8 samples were at high risk ofcervical cancer (the risk probabilities were all over 85%), and 3 wereat low risk of cervical cancer (the risk probabilities were all lessthan 5%). Tracing back the sample sources of subjects predicted to behigh risk and subjects predicted to be low risk, it was found that 5samples with high risk of cervical cancer were obtained from patientswho were diagnosed as cervical cancer by other diagnostic methods. Threesamples with low risk of cervical cancer were obtained from healthyindividuals detected by other diagnostic methods.

The result is shown in FIG. 8 . In FIGS. 8 , P1, P2, P3, P4 and P5 were5 cervical cancer patients, P3, P4 and P5 were 3 of 9 cervical cancersamples in training set, and P1 and P2 were cervical cancer samples notin model training set; H1, H2 and H3 were all samples of non-cervicalcancer healthy individuals.

Therefore, the method and the gene classifier of the present disclosurecan effectively distinguish cervical cancer patients from healthyindividuals.

Example 10: Typing of Cervical Cancer Patients Using ErythrocyteMicronuclei DNA

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Using the classifier (360 genes) constructed in Example 7 for clusteringpatients with cervical squamous cell carcinoma and cervicaladenocarcinoma, three cervical cancer samples with unknownclassification were predicted.

After testing, it was found that two of the three samples were of highrisk (the risk probabilities were all over 85%) and one was of low risk(the risk probability was less than 5%). Tracing back the sample sourcesof subjects with high risk of cervical squamous cell carcinoma andsubjects with low risk of cervical squamous cell carcinoma, it was foundthat two samples with high risk of cervical squamous cell carcinoma wereobtained from patients with cervical squamous cell carcinoma detected byother diagnostic methods, and one sample with low risk of cervicalsquamous cell carcinoma was obtained from healthy individuals asdetected by other diagnostic methods.

The result is shown in FIG. 9 . In FIG. 9 , P1 was a patient withcervical adenocarcinoma, and P2 and P3 were patients with cervicalsquamous cell carcinoma.

Therefore, the method and gene classifier of the present disclosure caneffectively classify cervical cancer patients and distinguish cervicalsquamous cell carcinoma from cervical adenocarcinoma.

Example 11: Construction of a Classifier for Classifying HealthyIndividuals and Colorectal Cancer Patients Using Erythrocyte MicronucleiDNA

In this Example, there were 17 subjects, including:

Experimental group: 4 patients diagnosed as colorectal cancer by othermethods

Control group: 13 healthy individuals (non-colorectal cancerindividuals).

The peripheral blood samples from patients with colorectal cancer wereexpressed in the form of “P” plus patient number. For example, “P1”represented a peripheral blood sample from the first colorectal cancerpatient (“Patient 1”), “P2” represented a peripheral blood sample fromthe second colorectal cancer patient (“Patient 2”), and so on. Inaddition, peripheral blood samples from healthy individuals wereexpressed in the form of “H” plus individual number. For example, “H1”represents the peripheral blood sample from the first healthyindividual, “H2” represents the peripheral blood sample from the secondhealthy individual, and so on.

The basic information of 4 patients with colorectal cancer is shown inTable 7. Colorectal cancer type, e.g., “adenocarcinoma”, refers to thetype of colorectal cancer diagnosed by other methods.

TABLE 7 Patient Enteroscopy number Gender Complaint pathology 1 FemaleIncreased stool frequency (sigmoid colon) with bloody stool for lowdifferentiated more than 2 months adenocarcinoma 2 Female Black stoolfor more Adenocarcinoma than 2 months (65 cm from anus) 3 Male Rectalcancer was Adenocarcinoma diagnosed for (rectum) more than 1 month 4Male Latent pain in the left (40 cm from anus) villous lower abdomen for1 adenoma, high-grade week intraepithelial neoplasia, and focalCancerization cannot be excluded

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Specifically, the reads counts of the gene regions of 4 primarycolorectal cancer samples and 13 healthy female samples were selected,and 903 differential genes were screened out by ANOVA test todistinguish the two classes of samples. Then, the unsupervisedhierarchical clustering of the two classes of samples was carried outaccording to Pearson correlation, and it was found that there weresignificant differences between the two classes of samples.

As shown in FIG. 10 , red cell micronuclei DNA from peripheral bloodsamples of colorectal cancer patients and red cell micronuclei DNA fromperipheral blood samples of healthy individuals were clustered to obtain903 differential genes (forming a classifier for distinguishing healthyindividuals from colorectal cancer patients). In FIG. 10 , each rowrepresents a differential gene, and each column represents a patient.

The list of 903 differential genes is shown in Table 8. Each genecorresponds to each row from top to bottom in FIG. 10 .

TABLE 8 1 FXYD3 2 CD9 3 DYNLL1 4 CTSA 5 PDCD6IP 6 IDH2 7 RBMX 8 CORO1B 9SLC12A2 10 RCC2 11 SETD3 12 PAPOLA 13 PLEC 14 DRG1 15 DTYMK 16 RBM47 17NFU1 18 DNAJB6 19 CDC42SE2 20 CCND2 21 EPHA2 22 STT3B 23 PITRM1 24 NARF25 WDR45 26 EXT2 27 LTBP4 28 HSPG2 29 OTUD5 30 COG4 31 NEK6 32 CCNK 33UBE3C 34 VDR 35 IGF2R 36 FOXA3 37 SH3BP4 38 LAMC1 39 SPPL2A 40 GBP2 41KREMEN1 42 PIP5K1B 43 FAF1 44 RAB9A 45 ALAD 46 PDE9A 47 CORO7 48 TFE3 49NEDD9 50 CCDC107 51 TMEM181 52 SLC1A4 53 HDAC7 54 MEMO1 55 ATRN 56 VWF57 MXI1 58 FOXK2 59 MCCC1 60 IPO8 61 EPS15 62 CCDC80 63 ACOT1 64 ABCB765 RANBP2 66 HS6ST1 67 PIP5K1C 68 PLXND1 69 MED27 70 SLC25A29 71 XIAP 72CCDC85C 73 ATP11A 74 AGFG1 75 BNIP2 76 LRRC32 77 WDR4 78 ISY1 79 RBM1980 CYBB 81 PARVA 82 UPF2 83 RECQL 84 UBIAD1 85 MICALL1 86 CRTC3 87 PEX188 PPP1R13B 89 GBP4 90 MCF2L 91 DCUN1D1 92 CBWD6 93 IFNAR2 94 HAUS2 95IGSF9 96 PTPRE 97 CCDC120 98 JMJD1C 99 RLIM 100 TRAPPC2 101 MSRA 102TRAF3IP1 103 MZF1 104 RAI1 105 C11orf80 106 SHF 107 LZTFL1 108 ASH1L 109PKD1 110 NFAT5 111 POFUT2 112 CD300A 113 CEMP1 114 SDR16C5 115 PTPRD 116ENOX2 117 ZSWIM7 118 CABLES1 119 ZNF74 120 MYPOP 121 ZNF91 122 CREB1 123CHRDL1 124 LIMS1 125 NOX4 126 CELSR1 127 SLA 128 PRKCH 129 ARID2 130PKD2 131 INVS 132 PASK 133 MSX1 134 FAM129A 135 TCF4 136 ABTB2 137 ZAP70138 RALGAPA1 139 HIVEP2 140 RIC8B 141 ORAI2 142 DUSP28 143 CSGALNACT1144 CDADC1 145 SEMA3A 146 ZBP1 147 ABI3BP 148 GAMT 149 KLHL13 150 EME1151 ANO7 152 PNMA5 153 ZFHX3 154 SLC13A3 155 SLC16A2 156 BDKRB1 157TOR1AIP2 158 USP45 159 LDLRAD2 160 ACTL8 161 TNNI3 162 SLIT3 163 TFAP2A164 TNRC6C 165 SPTLC3 166 ITPR1 167 ZNF222 168 EPHB1 169 PRICKLE2 170DMD 171 RASGEF1A 172 DTNA 173 ATAD3C 174 HHIPL1 175 ADAM33 176 CHAD 177WDR31 178 NRXN3 179 GPM6A 180 C22orf23 181 TBXA2R 182 SETBP1 183 CREB5184 SIRPB2 185 HECW2 186 GDPD1 187 ADAMTS5 188 TIAM1 189 PI15 190 TCEANC191 PDE10A 192 DYNC1I1 193 SNAP25 194 FASLG 195 GRIP1 196 MAP3K9 197LSAMP 198 SOX6 199 SCG3 200 CDKL3 201 CACNA2D1 202 CCDC157 203 FAM155A204 ADAMTS17 205 OPRL1 206 FUNDC2P2 207 ACSM1 208 ALPK2 209 SEMA5B 210PHACTR1 211 KRT12 212 UNC5A 213 JAKMIP1 214 DGKB 215 GRIN2B 216 CCDC17217 C8orf48 218 FAM163A 219 MYLK4 220 UGT2B10 221 ANKRD53 222 SH2D5 223KCNA2 224 CFC1B 225 OPCML 226 ANKS1B 227 ABCA4 228 RAB3B 229 ZNF732 230CTNND2 231 TTC24 232 PPM1E 233 GPC5 234 FBXO15 235 AR 236 LY6G6F 237GRIK4 238 CTNNA3 239 DDX53 240 TECTA 241 CCL16 242 TMC3 243 EPO 244PTPRT 245 KCTD8 246 CDH12 247 KCNQ3 248 CADM2 249 DAZL 250 GRM1 251SLC12A5 252 LRP1B 253 MED12L 254 OR14I1 255 CDH10 256 CNTN5 257 TMC1 258TRDN 259 ZNF716 260 MYT1L 261 GSX1 262 CSMD3 263 UNC13C 264 C20orf173265 KCNU1 266 DKFZp434L192 267 VSX2 268 C4orf22 269 KCNK16 270 FSD2 271CPXCR1 272 GRID2 273 ATP13A5 274 H1FOO 275 SPINK8 276 LEUTX 277 GFRA4278 IQCJ 279 KRTAP19-8 280 HTN3 281 TTC24 282 PPP4R3C 283 SYNDIG1 284TRAPPC2 285 OTUD5 286 RBMX 287 PDE10A 288 LINC00871 289 DNAJB6 290LOC101928254 291 GMNC 292 CSGALNACT1 293 LINC01581 294 AGFG1 295PLS3-AS1 296 LINC00972 297 FAF1 298 PPP4R3C 299 DMD 300 DAZL 301 TNNI3302 DMD 303 TNNI3 304 PIP5K1B 305 MEMO1 306 MZF1 307 PPM1E 308 ADAMTS5309 MED27 310 WDR45 311 PPP4R3C 312 MAP3K9 313 CDH12 314 DYNC1I1 315MAP3K9 316 LINC01019 317 GBP2 318 CADM2 319 SLA 320 SPTLC3 321 KCTD8 322SEMA3A 323 UNC13C 324 TFE3 325 XRCC6P5 326 RALGAPA1 327 CPXCR1 328 ALPK2329 XRCC6P5 330 LOC102724908 331 CCDC80 332 ALPK2 333 KCTD8 334 DTNA 335FAM129A 336 PDE9A 337 GRM1 338 CYBB 339 ZNF91 340 SYNDIG1 341 CPXCR1 342CPXCR1 343 PLCB1-IT1 344 RNA5-8SN5 345 GRM1 346 PNMA5 347 SYNDIG1 348CADM2 349 SYNDIG1 350 LINC00548 351 LOC101928012 352 LINC00972 353KLHL13 354 KCTD8 355 MIR5011 356 EPS15 357 GBP4 358 LEUTX 359 CCDC120360 DKFZp434L192 361 MAP3K21 362 NFU1 363 DMD 364 MAP3K9 365 LOC728739366 CPXCR1 367 PHACTR1 368 PPM1E 369 LINC00871 370 LOC101928012 371PDE10A 372 SLC16A2 373 XRCC6P5 374 SDR16C5 375 CSGALNACT1 376 LINC01317377 GBP4 378 RALGAPA1 379 GBP2 380 LINC00871 381 CPXCR1 382 ALPK2 383PPM1E 384 ATP13A5 385 CYBB 386 DMD 387 GRIP1 388 RLIM 389 LINC01467 390AR 391 ANKS1B 392 LINC00871 393 SDR16C5 394 MIR4675 395 ZFPM2-AS1 396LINC00972 397 RAB9A 398 ZFPM2-AS1 399 UNC13C 400 DMD 401 RALGAPA1 402CBWD6 403 ANKS1B 404 NFU1 405 PDE10A 406 CBWD6 407 SYNDIG1 408 NFU1 409CSGALNACT1 410 PDE10A 411 NXPE4 412 SLC12A2 413 CPXCR1 414 MAP3K21 415TCEANC 416 SLC16A2 417 MAP3K21 418 GBP2 419 ZFPM2-AS1 420 ABI3BP 421ANKS1B 422 TECTA 423 ALPK2 424 NRXN3 425 ABI3BP 426 JAKMIP1 427 ALB 428APOA2 429 HP 430 FTL 431 APOC1 432 APOA1 433 APOC3 434 ORM1 435 SERPINA1436 APOE 437 RBP4 438 FGA 439 AMBP 440 FGG 441 VTN 442 APOC2 443 APOH444 TF 445 TTR 446 B2M 447 FGB 448 C3 449 SAA1 450 FABP1 451 AHSG 452SERPINA3 453 RPLP1 454 CYP2E1 455 IFITM3 456 SERPINC1 457 ALDOB 458GAPDH 459 FTH1 460 MT2A 461 RPL8 462 HPX 463 ORM2 464 EPHX1 465 CLU 466SAA2 467 ACTB 468 H19 469 GC 470 CES1 471 RPL30 472 SERPING1 473 RPL37A474 PLG 475 RPS11 476 FGL1 477 HRG 478 RPL41 479 RPL19 480 SEPP1 481 CRP482 AGT 483 RARRES2 484 RPS12 485 KNG1 486 RPS16 487 RPS6 488 CFH 489RPS24 490 RPL3 491 TMSB10 492 P4HB 493 APCS 494 RPLP2 495 RPS20 496 UBB497 A1BG 498 MT1G 499 TMEM176B 500 CTSD 501 PEBP1 502 RPS8 503 RPS9 504RPLP0 505 ADH1B 506 RPS4X 507 RPL27 508 CD74 509 RPL11 510 RPS19 511DCXR 512 ACTG1 513 RPL23 514 RPL35 515 AGXT 516 C1S 517 AZGP1 518 RPL38519 RPL36 520 CALR 521 RPS14 522 RPS21 523 GLUL 524 IL32 525 ITIH2 526GNB2L1 527 F2 528 MGST1 529 PPIB 530 ITIH4 531 EEF1A1 532 GSTA1 533PRAP1 534 RPL18 535 TMEM176A 536 HPD 537 RPS5 538 RPL24 539 A2M 540 SOD1541 SOD2 542 RPL4 543 IGF2 544 MYL6 545 RPL35A 546 RPS15A 547 AKR1C1 548RPS25 549 RPL31 550 RPL29 551 FAU 552 HSPB1 553 MT1X 554 CYP2A6 555SERPINF2 556 RPL5 557 MIF 558 RPL7A 559 HMGCS2 560 CYP3A4 561 ATP5E 562CFHR1 563 ITIH1 564 COX7C 565 REG3A 566 RPL13A 567 SERPINF1 568 ASS1 569CD63 570 C4BPA 571 RPL26 572 C1R 573 RPS13 574 ITIH3 575 EEF2 576 FN1577 SQSTM1 578 ALDH2 579 KRT18 580 HINT1 581 ALDH1A1 582 RPL12 583RPL10A 584 UBC 585 TMBIM6 586 CYB5A 587 IGFBP1 588 PSAP 589 SPP1 590PLA2G2A 591 TPT1 592 GPX3 593 PTMS 594 IFI27 595 UGT2B4 596 SPINK1 597ENO1 598 IGFBP4 599 AKR1B10 600 SERPIND1 601 RPS10 602 ECHS1 603 ADH4604 ANG 605 RPS2 606 ASGR2 607 HSP90B1 608 COX4I1 609 CFL1 610 RPL14 611EDF1 612 COX6B1 613 EIF1 614 GATM 615 ADH1A 616 HULC 617 HSP90AB1 618LBP 619 RPL37 620 MT1E 621 SAA4 622 RPS7 623 IGFBP2 624 CFHR2 625 KRT8626 RPS27A 627 APOC4 628 PRDX1 629 RPS15 630 ASGR1 631 NNMT 632 RPL32633 PTMA 634 AKR1C3 635 SCD 636 APOB 637 RPS17 638 ATP5B 639 CD81 640EEF1G 641 NME2 642 CPS1 643 LASS2 644 OAZ1 645 PCK1 646 HPR 647 SDS 648TM4SF4 649 TIMP1 650 NDUFB9 651 TST 652 IFITM2 653 DHCR24 654 SERPINA6655 LYZ 656 PFN1 657 EEF1D 658 CPB2 659 PRDX6 660 NDUFA13 661 ATP5H 662PSMB4 663 CP 664 COX6A1 665 ADH1C 666 ETFB 667 NUPR1 668 ATP5I 669 HSPA8670 ATF5 671 RPS18 672 ECH1 673 GPX4 674 RPL17 675 RPL34 676 PFDN5 677GPX2 678 PABPC1 679 TXN 680 TAGLN2 681 LRG1 682 MYL12B 683 RPL6 684HRSP12 685 DDT 686 COX5B 687 HSD17B6 688 COX7B 689 COX8A 690 CHI3L1 691GSTK1 692 TAT 693 RPS3 694 MAT1A 695 SULT2A1 696 AFP 697 CTSB 698 ALDOA699 PAH 700 RPL15 701 GAMT 702 ATOX1 703 XBP1 704 BTF3 705 GRHPR 706PRDX5 707 CYP2C9 708 GABARAP 709 DBI 710 C8G 711 TPI1 712 KRTCAP2 713GPX1 714 SHFM1 715 ADI1 716 SDC1 717 CYP27A1 718 TFR2 719 APOA4 720RPL36AL 721 F12 722 HSPD1 723 NDUFA1 724 RPL10 725 MASP2 726 LDHA 727ARG1 728 TUBA1B 729 ARF1 730 TM4SF5 731 CD14 732 BSG 733 SSR2 734 CYP2D6735 GSTO1 736 COX6C 737 DEFB1 738 ATP5J2 739 POR 740 SAT1 741 PNKD 742GJB1 743 GRINA 744 LGALS4 745 SLC25A5 746 PSMB3 747 HSPA5 748 HSD11B1749 HAMP 750 CHCHD2 751 RHOB 752 GNAS 753 TFPI 754 ITM2B 755 C4BPB 756OST4 757 SLC38A3 758 BAAT 759 LCN2 760 REEP6 761 PTGR1 762 SERPINA5 763CFB 764 SEPHS2 765 SLC25A3 766 GPC3 767 UBL5 768 PTGDS 769 PGRMC1 770CTSZ 771 ACADVL 772 CYP2C8 773 EIF5A 774 EEF1B2 775 FBP1 776 AKR1C4 777PARK7 778 EFNA1 779 CALM2 780 FDPS 781 SEC61B 782 LGALS1 783 MPST 784RPSAP58 785 SLPI 786 INSIG1 787 SLC27A5 788 NDUFB7 789 IGFBP7 790 PRDX2791 TCEB2 792 MYL12A 793 ATP5A1 794 NPM1 795 ALDH1L1 796 LGALS3BP 797HSPE1 798 RPSA 799 PSME1 800 PCBP1 801 ATP5G2 802 EBP 803 ANXA2 804 HPN805 PSME2 806 PCK2 807 GUK1 808 HSP90AA1 809 PLIN2 810 PSMD4 811 CYP4A11812 TGM2 813 NDUFS5 814 PDIA3 815 BLVRB 816 GSTA2 817 ATP5C1 818 ACAA2819 CFI 820 IFI6 821 LMAN2 822 TMED9 823 PON1 824 NUCB1 825 PHYH 826ADAM6 827 FMO3 828 ADH6 829 ERBB3 830 UGT2B7 831 ATPIF1 832 HIST1H1C 833BCAP31 834 SSR4 835 HGD 836 UQCRQ 837 AADAC 838 OS9 839 NDUFB2 840 ATP5O841 IFI30 842 EIF4A1 843 DAD1 844 TALDO1 845 CHCHD10 846 ANGPTL4 847EIF3K 848 FIS1 849 UQCRC1 850 BST2 851 PROC 852 RPL23A 853 DECR1 854 CAT855 UGT1A6 856 ATP6V0E1 857 COL18A1 858 CANX 859 ANPEP 860 C1orf43 861DYNLL1 862 YBX1 863 AOX1 864 SCP2 865 PDIA6 866 BHMT 867 CES2 868 PSMB1869 AQP9 870 HDGF 871 ACSL1 872 CYC1 873 FTCD 874 EIF6 875 PCBD1 876NDUFS6 877 NACA 878 STARD10 879 RPN1 880 LAMP1 881 BRI3 882 C11orf10 883RHOA 884 CD151 885 TMEM59 886 RNASE4 887 CCT3 888 NCRNA00188 889 HLA-B890 ACAA1 891 CAPNS1 892 APLP2 893 SDC4 894 HIST1H2AC 895 RPS29 896ATP5D 897 SELENBP1 898 RPN2 899 GLUD1 900 PSMA7 901 ST6GAL1 902 SNRPD2903 MLF2

Example 12: Construction of a Classifier for the Typing of ColorectalCancer Patients Using Erythrocyte Micronuclei DNA

In this Example, there were 10 patients with colorectal cancer,including 5 patients diagnosed with colon cancer and 5 patientsdiagnosed with rectal cancer by other methods.

The peripheral blood samples from the above patients are expressed inthe form of “P” plus patient number. For example, “P1” represents aperipheral blood sample from the first colorectal cancer patient(“Patient 1”), “P2” represents a peripheral blood sample from the secondcolorectal cancer patient (“Patient 2”), and so on.

The basic information of 10 colorectal cancer patients is shown in Table9. Colorectal cancer type, e.g., “adenocarcinoma”, refers to the type ofcolorectal cancer diagnosed by other methods.

TABLE 9 Patient number Gender Complaint Enteroscopy pathology 1 MaleRectal cancer was Adenocarcinoma (rectum) diagnosed for more than 1month 2 Female The stool habit (rectal) villous adenoma with low-gradechanged for more intraepithelial neoplasia, local high-grade than half ayear intraepithelial neoplasia, the lesion was confined to the laminapropria, and no submucosal infiltration was found. It was recommended tobiopsy again to exclude Cancerization. 3 Male Changes in stool Mediumdifferentiated adenocarcinoma (rectum) characteristics with hematocheziafor more than 3 months 4 Female Rectal cancer was Medium differentiatedadenocarcinoma (rectum) diagnosed for more than 3 months 5 Male CEAgradually Adenocarcinoma (rectum) increased for more than 9 months 6Male After more than 1 Medium differentiated adenocarcinoma month ofhematochezia, (sigmoid colon) colon cancer was diagnosed for 4 days. 7Male Blood in stool for 1 (sigmoid colon) The broken mucosa showed weekhigh-grade intraepithelial neoplasia. Cancerization cannot be excluded.8 Female Repeated abdominal Adenocarcinoma of colon pain for more than 2months 9 Female Diarrhea and (colon biopsy) low differentiatedhematochezia for three adenocarcinoma months, and fatigue for one month10 Female Colonic tumor was Considered as adenocarcinoma (livercurvature found for 1 week of colon).

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Specifically, 97 different genes were screened out by ANOVA test fromthe reads count of gene regions of 5 colon cancer samples and 5 rectalcancer samples, and then unsupervised hierarchical clustering of the twotypes of samples according to Pearson correlation showed that there weresignificant differences between the two classes of samples.

As shown in FIG. 11 , a total of 97 genes from colon cancer and rectalcancer samples were clustered. Each row represents a differential gene,and each column represents a patient.

The list of 97 differential genes is shown in Table 10. Each genecorresponds to each row from top to bottom in FIG. 12 .

TABLE 10 1 FXYD3 2 CD9 3 DYNLL1 4 CTSA 5 CCDC107 6 TMEM181 7 SLC1A4 8HDAC7 9 MEMO1 10 ATRN 11 VWF 12 MXI1 13 FOXK2 14 MCCC1 15 PAPOLA 16 PLEC17 DRG1 18 DTYMK 19 RBM47 20 NFU1 21 DNAJB6 22 CDC42SE2 23 CCND2 24EPHA2 25 STT3B 26 PITRM1 27 LTBP4 28 HSPG2 29 OTUD5 30 COG4 31 NEK6 32CCNK 33 UBE3C 34 VDR 35 IGF2R 36 FOXA3 37 SH3BP4 38 LAMC1 39 SPPL2A 40GBP2 41 KREMEN1 42 PIP5K1B 43 FAF1 44 RAB9A 45 ALAD 46 PDE9A 47 CORO7 48TFE3 49 NEDD9 50 PDCD6IP 51 IDH2 52 RBMX 53 CORO1B 54 SLC12A2 55 RCC2 56SETD3 57 NARF 58 WDR45 59 EXT2 60 IPO8 61 EPS15 62 CCDC80 63 ACOT1 64ABCB7 65 RANBP2 66 HS6ST1 67 PIP5K1C 68 PLXND1 69 MED27 70 SLC25A29 71XIAP 72 CCDC85C 73 ATP11A 74 AGFG1 75 BNIP2 76 LRRC32 77 WDR4 78 ISY1 79RBM19 80 CYBB 81 PARVA 82 UPF2 83 RECQL 84 UBIAD1 85 MICALL1 86 CREB1 87CHRDL1 88 LIMS1 89 NOX4 90 CELSR1 91 SLA 92 PRKCH 93 ARID2 94 PKD2 95INVS 96 PASK 97 MSX1

Example 13. Classification of Healthy Individuals and Colorectal CancerPatients Using Erythrocyte Micronuclei DNA

Using the classifier (903 genes) constructed in Example 11 forclustering healthy individuals and colorectal cancer patients, fourunknown samples from four subjects were predicted.

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

After testing, it was found that two of the four samples were at highrisk of colorectal cancer (the risk probabilities were all over 90%) andtwo were at low risk of colorectal cancer (the risk probabilities wereall less than 5%). Tracing back the sample sources of subjects predictedto be high risk and subjects predicted to be low risk, it was found thatthe two samples with high risk of colorectal cancer were obtained frompatients who were diagnosed as colorectal cancer by other diagnosticmethods, and the two samples with low risk of colorectal cancer wereobtained from healthy individuals detected by other diagnostic methods.

The result is shown in FIG. 12 . In FIGS. 12 , P1 and P2 were twopatients with colorectal cancer, and H1 and H2 were samples ofnon-colorectal cancer healthy individuals.

Therefore, the method and gene classifier of the present disclosure caneffectively distinguish colorectal cancer patients from healthyindividuals.

Example 14. Typing of Colorectal Cancer Patients Using ErythrocyteMicronuclei DNA

Erythrocyte micronuclei DNA and genomic DNA of peripheral bloodmononuclear cells of each subject were obtained as described in Examples1-4, and bioinformatics analysis was carried out as described in Example5.

Using the classifier (97 genes) constructed in Example 12 for clusteringcolon cancer and rectal cancer patients, four colorectal cancer sampleswith unknown classification were predicted.

After testing, it was found that two of the four samples were at highrisk of colon cancer (the risk probabilities were all over 85%) and twowere at low risk of colon cancer (the risk probabilities were all lessthan 5%). Tracing back the sample sources of subjects with high risk ofcolon cancer and subjects with low risk of colon cancer, it was foundthat the two samples with high risk of colon cancer were obtained frompatients with colon cancer detected by other diagnostic methods, and thetwo samples with low risk of colon cancer came from subjects who werediagnosed as rectal cancer by other diagnostic methods.

The result is shown in FIG. 13 . In FIGS. 13 , P1 and P2 are coloncancer patients, and P2 and P3 are rectal cancer patients.

Therefore, the method and gene classifier of the present disclosure caneffectively classify colorectal cancer patients and distinguish coloncancer from rectal cancer.

Example 15. Discriminative Performance of the rbcDNA Signature in CancerPatients

We randomly assigned HD and cancer samples to a training set (70%,n=236) for model development, a validation set (10%, n=34) forhyper-parameter selection and a test set (20%, n=68) for modelvalidation. Our results showed that 91% (95% confidence interval84-100%) of cancer patients including 85% LC, 100% CRC and 90% HCC weredetected with 99% specificity. This includes 86% patients with stage I,92% of patients with stage II and 100% of patients with stage IIIcancers (Table 14). This data suggests the presence of specific rbcDNAsignatures that can differentiate between healthy donors and cancerpatients. We next tested the efficacy of rbcDNA in differentiating amongspecific cancer types. rbcDNA signatures exhibit high discriminatoryperformance in pairwise comparisons of healthy and cancer groups, ourresults showed that 90% (95% confidence interval 68-100%) of HCCpatients, 100% (95% confidence interval 100-100%) of CRC patients and85% (95% confidence interval 70-100%) of LC patients, all were detectedwith 95% specificity (Table 15). Moreover, pairwise and multiclass testsshowed overall high accuracy in detecting specific cancers indicatingsignificant discriminative power of rbcDNA profiles (FIG. 14 ).

The result is shown in Table 14, the list of differential rbcDNAsignature is shown in Table 16.

The result is shown in Table 15, the list of differential rbcDNAsignature is shown in Table 17 for HD vs. LC, Table 18 for HD vs. CRC,Table 19 for HD vs. HCC.

The result is shown in FIG. 15 , the list of differential rbcDNAsignature is shown in Table 20.

TABLE 14 Pan-Cancer analysed 99% specificity Test Individual Sensitivity95% CI (Total) detected (%) (%) HD 21 (106) 0 Cancer 47 (232) 43 9184-100 Type HCC 9 (44) 8 90 68-100 CRC 18 (99) 18 100 100-100  LC 20(89) 17 85 69-100 Stage I 22 (106) 19 86 72-100 II 12 (61) 11 92 76-100III 13 (65) 13 100 100-100 

TABLE 15 95% specificity Test Individual Cancer Type (Total) detectedSensitivity 95% CI HCC 9 8 90 68-100 CRC 18 18 100 100-100  LC 20 17 8570-100

Table 14 shows accuracy ratios of pan-cancer deep neural networkclassification in the test set for each cancer type, includingcorresponding sensitivity with 99% specificity (CI, ConfidenceInterval).

Table 15 shows accuracy ratios of each cancer type deep neural networkclassification in the test set for each cancer type, includingcorresponding sensitivity with 95% specificity (CI, ConfidenceInterval).

TABLE 16 1 chr1: 500000-1000000, chr1: 1500000-2000000, chr1:2500000-3000000, chr1: 8000000-8500000, chr1: 8500000-9000000, chr1:9500000-10000000, chr1: 10000000-10500000, chr1: 11500000- 12000000,chr1: 12000000-12500000, chr1: 13000000-13500000, chr1:15500000-16000000, chr1: 16000000-16500000, chr1: 16500000-17000000,chr1: 19000000-19500000, chr1: 19500000- 20000000, chr1:20000000-20500000, chr1: 20500000-21000000, chr1: 21000000-21500000,chr1: 23000000-23500000, chr1: 24500000-25000000, chr1:25500000-26000000, chr1: 26000000- 26500000, chr1: 26500000-27000000,chr1: 27000000-27500000, chr1: 27500000-28000000, chr1:28000000-28500000, chr1: 28500000-29000000, chr1: 30500000-31000000,chr1: 31500000- 32000000, chr1: 32000000-32500000, chr1:32500000-33000000, chr1: 33000000-33500000, chr1: 33500000-34000000,chr1: 35500000-36000000, chr1: 36000000-36500000, chr1: 36500000-37000000, chr1: 37500000-38000000, chr1: 38500000-39000000, chr1:39000000-39500000, chr1: 40000000-40500000, chr1: 40500000-41000000,chr1: 42000000-42500000, chr1: 44500000- 45000000, chr1:45500000-46000000, chr1: 51500000-52000000, chr1: 52500000-53000000chr1: 53500000-54000000, chr1: 54000000-54500000, chr1:58500000-59000000, chr1: 59000000- 59500000, chr1: 61000000-61500000,chr1: 63500000-64000000, chr1: 64500000-65000000, chr1:65000000-65500000, chr1: 66000000-66500000, chr1: 77000000-77500000,chr1: 77500000- 78000000, chr1: 83000000-83500000, chr1:88500000-89000000, chr1: 91500000-92000000, chr1: 94500000-95000000,chr1: 98500000-99000000, chr1: 101000000-101500000, chr1:107500000-108000000, chr1: 108500000-109000000, chr1:109000000-109500000, chr1: 109500000-110000000, chr1:110500000-111000000, chr1: 111500000-112000000, chr1:112500000-113000000, chr1: 114000000-114500000, chr1:116000000-116500000, chr1: 116500000-117000000, chr1:120000000-120500000, chr1: 120500000-121000000, chr1:121000000-121500000, chr1: 125000000-125500000, chr1:143000000-143500000, chr1: 143500000-144000000, chr1:144000000-144500000, chr1: 144500000-145000000, chr1:145000000-145500000, chr1: 146000000-146500000, chr1:146500000-147000000, chr1: 147500000-148000000, chr1:148000000-148500000, chr1: 148500000-149000000, chr1:149000000-149500000, chr1: 149500000-150000000, chr1:150000000-150500000, chr1: 150500000-151000000, chr1:151000000-151500000, chr1: 151500000-152000000, chr1:153500000-154000000, chr1: 154000000-154500000, chr1:154500000-155000000, chr1: 155000000-155500000, chr1:155500000-156000000, chr1: 156000000-156500000, chr1:156500000-157000000, chr1: 158000000-158500000, chr1:159000000-159500000, chr1: 160000000-160500000, chr1:160500000-161000000, chr1: 161000000-161500000, chr1:162000000-162500000, chr1: 163500000-164000000, chr1:165500000-166000000, chr1: 167000000-167500000, chr1:169500000-170000000, chr1: 171000000-171500000, chr1:171500000-172000000, chr1: 172500000-173000000, chr1:173500000-174000000, chr1: 177500000-178000000, chr1:181000000-181500000, chr1: 182000000-182500000, chr1:182500000-183000000, chr1: 183000000-183500000, chr1:193000000-193500000, chr1: 197000000-197500000, chr1:198500000-199000000, chr1: 199000000-199500000, chr1:200000000-200500000, chr1: 200500000-201000000, chr1:202500000-203000000, chr1: 203000000-203500000, chr1:203500000-204000000, chr1: 204000000-204500000, chr1:205000000-205500000, chr1: 206500000-207000000, chr1:208000000-208500000, chr1: 211500000-212000000, chr1:212500000-213000000, chr1: 214000000-214500000, chr1:221500000-222000000, chr1: 222500000-223000000, chr1:225500000-226000000, chr1: 226000000-226500000, chr1:230500000-231000000, chr1: 235000000-235500000, chr1:235500000-236000000, chr1: 242000000-242500000, chr1:242500000-243000000, chr1: 243500000-244000000, chr1:246500000-247000000, chr1: 247000000-247500000 2 chr2:24500000-25000000, chr2: 25000000-25500000, chr2: 25500000-26000000,chr2: 26000000- 26500000, chr2: 27000000-27500000, chr2:27500000-28000000, chr2: 28500000-29000000, chr2: 36500000-37000000,chr2: 37000000-37500000, chr2: 37500000-38000000, chr2: 38500000-39000000, chr2: 39000000-39500000, chr2: 42000000-42500000, chr2:45500000-46000000, chr2: 48000000-48500000, chr2: 60500000-61000000,chr2: 61000000-61500000, chr2: 61500000- 62000000, chr2:64000000-64500000, chr2: 64500000-65000000, chr2: 65000000-65500000,chr2: 68000000-68500000, chr2: 69500000-70000000, chr2:70000000-70500000, chr2: 70500000- 71000000, chr2: 71000000-71500000,chr2: 72500000-73000000, chr2: 73500000-74000000, chr2:74500000-75000000, chr2: 76000000-76500000, chr2: 79000000-79500000,chr2: 84500000- 85000000, chr2: 87000000-87500000, chr2:87500000-88000000, chr2: 89000000-89500000, chr2: 89500000-90000000,chr2: 90000000-90500000, chr2: 91000000-91500000, chr2: 91500000-92000000, chr2: 92000000-92500000, chr2: 94500000-95000000, chr2:95500000-96000000, chr2: 96000000-96500000, chr2: 97000000-97500000,chr2: 102000000-102500000, chr2: 107500000-108000000, chr2:109500000-110000000, chr2: 110000000-110500000, chr2:112500000-113000000, chr2: 113500000-114000000, chr2:116000000-116500000, chr2: 119500000-120000000, chr2:122000000-122500000, chr2: 126500000-127000000, chr2:129000000-129500000, chr2: 130000000-130500000, chr2:131500000-132000000, chr2: 132000000-132500000, chr2:132500000-133000000, chr2: 135500000-136000000, chr2:136000000-136500000, chr2: 143000000-143500000, chr2:144000000-144500000, chr2: 144500000-145000000, chr2:148500000-149000000, chr2: 150000000-150500000, chr2:156000000-156500000, chr2: 158000000-158500000, chr2:162000000-162500000, chr2: 165500000-166000000, chr2:168000000-168500000, chr2: 168500000-169000000, chr2:171500000-172000000, chr2: 174500000-175000000, chr2:177000000-177500000, chr2: 178000000-178500000, chr2:181000000-181500000, chr2: 181500000-182000000, chr2:190000000-190500000, chr2: 190500000-191000000, chr2:191000000-191500000, chr2: 196000000-196500000, chr2:197000000-197500000, chr2: 200500000-201000000, chr2:201000000-201500000, chr2: 201500000-202000000, chr2:203000000-203500000, chr2: 207000000-207500000, chr2:207500000-208000000, chr2: 208500000-209000000, chr2:210000000-210500000, chr2: 216000000-216500000, chr2:217500000-218000000, chr2: 218000000-218500000, chr2:218500000-219000000, chr2: 219000000-219500000, chr2:224500000-225000000, chr2: 225000000-225500000, chr2:228000000-228500000, chr2: 230000000-230500000, chr2:230500000-231000000, chr2: 235500000-236000000, chr2:238500000-239000000, chr2: 240500000-241000000 3 chr3: 500000-1000000,chr3: 9000000-9500000, chr3: 9500000-10000000, chr3: 10000000- 10500000,chr3: 12500000-13000000, chr3: 13500000-14000000, chr3:14000000-14500000, chr3: 17000000-17500000, chr3: 17500000-18000000,chr3: 23500000-24000000, chr3: 30500000- 31000000, chr3:31500000-32000000, chr3: 32000000-32500000, chr3: 32500000-33000000,chr3: 36000000-36500000, chr3: 39000000-39500000, chr3:43500000-44000000, chr3: 47000000- 47500000, chr3: 47500000-48000000,chr3: 48500000-49000000, chr3: 49000000-49500000, chr3:49500000-50000000, chr3: 51500000-52000000, chr3: 52000000-52500000,chr3: 56500000- 57000000, chr3: 57500000-58000000, chr3:59000000-59500000, chr3: 64500000-65000000, chr3: 66000000-66500000,chr3: 69000000-69500000, chr3: 70000000-70500000, chr3: 71000000-71500000, chr3: 72000000-72500000, chr3: 75000000-75500000, chr3:75500000-76000000, chr3: 76500000-77000000, chr3: 88000000-88500000,chr3: 91000000-91500000, chr3: 101500000- 102000000, chr3:107500000-108000000, chr3: 119500000-120000000, chr3: 122000000-122500000, chr3: 127000000-127500000, chr3: 129500000-130000000, chr3:135500000- 136000000, chr3: 136500000-137000000, chr3:141500000-142000000, chr3: 143000000- 143500000, chr3:143500000-144000000, chr3: 150000000-150500000, chr3: 151000000-151500000, chr3: 156500000-157000000, chr3: 157000000-157500000, chr3:161000000- 161500000, chr3: 169500000-170000000, chr3:170000000-170500000, chr3: 171000000 171500000, chr3:172000000-172500000, chr3: 179500000-180000000, chr3: 184000000-184500000, chr3: 184500000-185000000, chr3: 185500000-186000000, chr3:186000000- 186500000, chr3: 186500000-187000000, chr3:188000000-188500000, chr3: 189000000- 189500000, chr3:194500000-195000000, chr3: 198000000-198295559 4 chr4: 2500000-3000000,chr4: 8500000-9000000, chr4: 9000000-9500000, chr4: 15000000- 15500000,chr4: 21000000-21500000, chr4: 26000000-26500000, chr4:36000000-36500000, chr4: 37500000-38000000, chr4: 38000000-38500000,chr4: 38500000-39000000, chr4: 39500000- 40000000, chr4:40000000-40500000, chr4: 40500000-41000000, chr4: 45000000-45500000,chr4: 48500000-49000000, chr4: 49000000-49500000, chr4:49500000-50000000, chr4: 61500000- 62000000, chr4: 70500000-71000000,chr4: 77500000-78000000, chr4: 78500000-79000000, chr4:80000000-80500000, chr4: 81500000-82000000, chr4: 83000000-83500000,chr4: 88500000- 89000000, chr4: 98500000-99000000, chr4:99500000-100000000, chr4: 102000000-102500000, chr4:108000000-108500000, chr4: 111000000-111500000, chr4:113500000-114000000, chr4: 121500000-122000000, chr4:126500000-127000000, chr4: 131500000-132000000, chr4:139000000-139500000, chr4: 142000000-142500000, chr4:146000000-146500000, chr4: 152000000-152500000, chr4:152500000-153000000, chr4: 153000000-153500000, chr4:153500000-154000000, chr4: 158500000-159000000, chr4:167000000-167500000, chr4: 172500000-173000000, chr4:184500000-185000000, chr4: 187000000-187500000, chr4:189500000-190000000, chr4: 190000000-190214555 5 chr5: 7000000-7500000,chr5: 9000000-9500000, chr5: 9500000-10000000, chr5: 10500000- 11000000,chr5: 17500000-18000000, chr5: 21000000-21500000, chr5:26000000-26500000, chr5: 34000000-34500000, chr5: 36500000-37000000,chr5: 39000000-39500000, chr5: 50500000- 51000000, chr5:51000000-51500000, chr5: 56000000-56500000, chr5: 56500000-57000000,chr5: 59000000-59500000, chr5: 59500000-60000000, chr5:68000000-68500000, chr5: 69500000- 70000000, chr5: 70000000-70500000,chr5: 70500000-71000000, chr5: 71000000-71500000, chr5:80000000-80500000, chr5: 80500000-81000000, chr5: 87000000-87500000,chr5: 91000000- 91500000, chr5: 94500000-95000000, chr5:96500000-97000000, chr5: 102500000-103000000, chr5: 109500000-110000000,chr5: 112000000-112500000, chr5: 112500000-113000000, chr5:115500000-116000000, chr5: 119000000-119500000, chr5:124000000-124500000, chr5: 125000000-125500000, chr5:126500000-127000000, chr5: 131000000-131500000, chr5:132000000-132500000, chr5: 133500000-134000000, chr5:136500000-137000000, chr5: 138000000-138500000, chr5:138500000-139000000, chr5: 139500000-140000000, chr5:140500000-141000000, chr5: 141000000-141500000, chr5:141500000-142000000, chr5: 142000000-142500000, chr5:142500000-143000000, chr5: 143000000-143500000, chr5:146000000-146500000, chr5: 148500000-149000000, chr5:151500000-152000000, chr5: 157000000-157500000, chr5:157500000-158000000, chr5: 158500000-159000000, chr5:159000000-159500000, chr5: 160000000-160500000, chr5:166500000-167000000, chr5: 169500000-170000000, chr5:170000000-170500000, chr5: 172000000-172500000, chr5:172500000-173000000, chr5: 177000000-177500000, chr5:181000000-181500000 6 chr6: 2500000-3000000, chr6: 6500000-7000000,chr6: 8500000-9000000, chr6: 11000000- 11500000, chr6:13000000-13500000, chr6: 13500000-14000000, chr6: 14000000-14500000,chr6: 14500000-15000000, chr6: 15000000-15500000, chr6:16000000-16500000, chr6: 17500000- 18000000, chr6: 25500000-26000000,chr6: 26000000-26500000, chr6: 29500000-30000000, chr6:30000000-30500000, chr6: 30500000-31000000, chr6: 31000000-31500000,chr6: 31500000- 32000000, chr6: 32000000-32500000, chr6:32500000-33000000, chr6: 33000000-33500000, chr6: 33500000-34000000,chr6: 34500000-35000000, chr6: 36000000-36500000, chr6: 36500000-37000000, chr6: 37000000-37500000, chr6: 37500000-38000000, chr6:40500000-41000000, chr6: 41000000-41500000, chr6: 41500000-42000000,chr6: 42500000-43000000, chr6: 43000000- 43500000, chr6:44000000-44500000, chr6: 53000000-53500000, chr6: 53500000-54000000,chr6: 57500000-58000000, chr6: 58000000-58500000, chr6:58500000-59000000, chr6: 60000000- 60500000, chr6: 60500000-61000000,chr6: 61000000-61500000, chr6: 73000000-73500000, chr6:77500000-78000000, chr6: 86000000-86500000, chr6: 87000000-87500000,chr6: 87500000- 88000000, chr6: 88500000-89000000, chr6:89000000-89500000, chr6: 106000000-106500000, chr6: 108500000-109000000,chr6: 110500000-111000000, chr6: 111500000-112000000, chr6:112000000-112500000, chr6: 112500000-113000000, chr6:119000000-119500000, chr6: 119500000-120000000, chr6:128000000-128500000, chr6: 129500000-130000000, chr6:130500000-131000000, chr6: 135000000-135500000, chr6:135500000-136000000, chr6: 137000000-137500000, chr6:137500000-138000000, chr6: 138000000-138500000, chr6:139000000-139500000, chr6: 142000000-142500000, chr6:143500000-144000000, chr6: 144000000-144500000, chr6:144500000-145000000, chr6: 149000000-149500000, chr6:149500000-150000000, chr6: 154000000-154500000, chr6:159500000-160000000 7 chr7: 3000000-3500000, chr7: 4000000-4500000,chr7: 6000000-6500000, chr7: 7500000-8000000, chr7: 26000000-26500000,chr7: 27000000-27500000, chr7: 30000000-30500000, chr7: 37000000-37500000, chr7: 39500000-40000000, chr7: 44500000-45000000, chr7:45500000-46000000, chr7: 46000000-46500000, chr7: 51500000-52000000,chr7: 54000000-54500000, chr7: 56500000- 57000000, chr7:57000000-57500000, chr7: 57500000-58000000, chr7: 58000000-58500000,chr7: 63000000-63500000, chr7: 63500000-64000000, chr7:65000000-65500000, chr7: 66500000- 67000000, chr7: 72000000-72500000,chr7: 72500000-73000000, chr7: 73500000-74000000, chr7:74000000-74500000, chr7: 74500000-75000000, chr7: 75500000-76000000,chr7: 76500000- 77000000, chr7: 77500000-78000000, chr7:92500000-93000000, chr7: 97500000-98000000, chr7: 98000000-98500000,chr7: 99000000-99500000, chr7: 100000000-100500000, chr7:100500000-101000000, chr7: 101000000-101500000, chr7:102500000-103000000, chr7: 105000000-105500000, chr7:106000000-106500000, chr7: 107000000-107500000, chr7:112000000-112500000, chr7: 127500000-128000000, chr7:128000000-128500000, chr7: 129000000-129500000, chr7:129500000-130000000, chr7: 130000000-130500000, chr7:133000000-133500000, chr7: 135500000-136000000, chr7:139000000-139500000, chr7: 141500000-142000000, chr7:143000000-143500000, chr7: 148500000-149000000, chr7:151000000-151500000 8 chr8: 0-500000, chr8: 3000000-3500000, chr8:7000000-7500000, chr8: 7500000-8000000, chr8: 8000000-8500000, chr8:12000000-12500000, chr8: 12500000-13000000, chr8: 17500000- 18000000,chr8: 20000000-20500000, chr8: 20500000-21000000, chr8:22500000-23000000, chr8: 27000000-27500000, chr8: 29000000-29500000,chr8: 30000000-30500000, chr8: 30500000- 31000000, chr8:35500000-36000000, chr8: 37500000-38000000, chr8: 42000000-42500000,chr8: 55000000-55500000, chr8: 58500000-59000000, chr8:60500000-61000000, chr8: 66500000- 67000000, chr8: 69000000-69500000,chr8: 70000000-70500000, chr8: 72000000-72500000, chr8:73500000-74000000, chr8: 74500000-75000000, chr8: 85500000-86000000,chr8: 91500000- 92000000, chr8: 94500000-95000000, chr8:96500000-97000000, chr8: 100000000-100500000, chr8: 103500000-104000000,chr8: 104000000-104500000, chr8: 120500000-121000000, chr8:122500000-123000000, chr8: 124000000-124500000, chr8:125000000-125500000, chr8: 130000000-130500000, chr8:133000000-133500000, chr8: 139500000-140000000, chr8:140000000-140500000, chr8: 140500000-141000000 9 chr9: 4500000-5000000,chr9: 5500000-6000000, chr9: 6500000-7000000, chr9: 15000000- 15500000,chr9: 17000000-17500000, chr9: 19000000-19500000, chr9:21000000-21500000, chr9: 21500000-22000000, chr9: 33000000-33500000,chr9: 34000000-34500000, chr9: 34500000- 35000000, chr9:35000000-35500000, chr9: 35500000-36000000, chr9: 36000000-36500000,chr9: 37500000-38000000, chr9: 39000000-39500000, chr9:39500000-40000000, chr9: 40000000- 40500000, chr9: 40500000-41000000,chr9: 41000000-41500000, chr9: 41500000-42000000, chr9:42000000-42500000, chr9: 42500000-43000000, chr9: 43000000-43500000,chr9: 60500000- 61000000, chr9: 61000000-61500000, chr9:61500000-62000000, chr9: 62000000-62500000, chr9: 62500000-63000000,chr9: 63000000-63500000, chr9: 63500000-64000000, chr9: 64000000-64500000, chr9: 64500000-65000000, chr9: 65000000-65500000, chr9:65500000-66000000, chr9: 66000000-66500000, chr9: 66500000-67000000,chr9: 67000000-67500000, chr9: 67500000- 68000000, chr9:77500000-78000000, chr9: 78500000-79000000, chr9: 80500000-81000000,chr9: 86500000-87000000, chr9: 89000000-89500000, chr9:92500000-93000000, chr9: 99000000- 99500000, chr9: 105000000-105500000,chr9: 114500000-115000000, chr9: 124500000- 125000000, chr9:125000000-125500000, chr9: 126000000-126500000, chr9: 127500000-128000000, chr9: 128000000-128500000, chr9: 128500000-129000000, chr9:129000000- 129500000, chr9: 129500000-130000000, chr9:132000000-132500000, chr9: 135000000- 135500000 10 chr10:3000000-3500000, chr10: 3500000-4000000, chr10: 4000000-4500000, chr10:6000000- 6500000, chr10: 8000000-8500000, chr10: 9000000-9500000, chr10:13500000-14000000, chr10: 20500000-21000000, chr10: 21500000-22000000,chr10: 27500000-28000000, chr10: 28000000-28500000, chr10:36500000-37000000, chr10: 37000000-37500000, chr10: 38000000-38500000,chr10: 38500000-39000000, chr10: 42000000-42500000, chr10:42500000-43000000, chr10: 43000000-43500000, chr10: 44000000-44500000,chr10: 46000000-46500000, chr10: 46500000-47000000, chr10:47500000-48000000, chr10: 52000000-52500000, chr10: 53500000-54000000,chr10: 55500000-56000000, chr10: 58000000-58500000, chr10:59000000-59500000, chr10: 62000000-62500000, chr10: 63000000-63500000,chr10: 68000000-68500000, chr10: 68500000-69000000, chr10:69000000-69500000, chr10: 72000000-72500000, chr10: 73000000-73500000,chr10: 79000000-79500000, chr10: 84500000-85000000, chr10:87000000-87500000, chr10: 88000000-88500000, chr10: 92500000-93000000,chr10: 94500000-95000000, chr10: 95000000-95500000, chr10:97000000-97500000, chr10: 97500000-98000000, chr10: 100000000-100500000,chr10: 100500000-101000000, chr10: 101000000-101500000, chr10:101500000-102000000, chr10: 102000000-102500000, chr10:102500000-103000000, chr10: 104000000-104500000, chr10:108000000-108500000, chr10: 109000000-109500000, chr10:109500000-110000000, chr10: 110500000-111000000, chr10:111500000-112000000, chr10: 119000000-119500000, chr10:125500000-126000000, chr10: 126500000-127000000, chr10:127000000-127500000, chr10: 128500000-129000000, chr10:129500000-130000000, chr10: 130000000-130500000, chr10:130500000-131000000, chr10: 133500000-133797422 11 chr11: 0-500000,chr11: 1500000-2000000, chr11: 3500000-4000000, chr11: 6000000-6500000,chr11: 6500000-7000000, chr11: 12000000-12500000, chr11:13000000-13500000, chr11: 18000000-18500000, chr11: 33000000-33500000,chr11: 34500000-35000000, chr11: 39500000-40000000, chr11:40000000-40500000, chr11: 44500000-45000000, chr11: 46000000-46500000,chr11: 47000000-47500000, chr11: 47500000-48000000, chr11:48500000-49000000, chr11: 49000000-49500000, chr11: 49500000-50000000,chr11: 50000000-50500000, chr11: 55500000-56000000, chr11:56500000-57000000, chr11: 57500000-58000000, chr11: 59500000-60000000,chr11: 61000000-61500000, chr11: 62000000-62500000, chr11:62500000-63000000, chr11: 63500000-64000000, chr11: 64500000-65000000,chr11: 65000000-65500000, chr11: 65500000-66000000, chr11:66000000-66500000, chr11: 67000000-67500000, chr11: 72000000-72500000,chr11: 72500000-73000000, chr11: 73000000-73500000, chr11:73500000-74000000, chr11: 77500000-78000000, chr11: 78000000-78500000,chr11: 86000000-86500000, chr11: 89000000-89500000, chr11:89500000-90000000, chr11: 92000000-92500000, chr11: 93000000-93500000,chr11: 95000000-95500000, chr11: 95500000-96000000, chr11:99500000-100000000, chr11: 100000000-100500000, chr11:101000000-101500000, chr11: 102000000-102500000, chr11:104000000-104500000, chr11: 104500000-105000000, chr11:109000000-109500000, chr11: 111500000-112000000, chr11:113500000-114000000, chr11: 114000000-114500000, chr11:118000000-118500000, chr11: 119000000-119500000, chr11:121000000-121500000, chr11: 122500000-123000000, chr11:128500000-129000000, chr11: 135000000-135086622 12 chr12:500000-1000000, chr12: 1500000-2000000, chr12: 6000000-6500000, chr12:6500000- 7000000, chr12: 8500000-9000000, chr12: 12000000-12500000,chr12: 12500000-13000000, chr12: 14500000-15000000, chr12:25500000-26000000, chr12: 29500000-30000000, chr12: 34500000-35000000,chr12: 37000000-37500000, chr12: 38000000-38500000, chr12:42000000-42500000, chr12: 47500000-48000000, chr12: 48500000-49000000,chr12: 49000000-49500000, chr12: 49500000-50000000, chr12:50000000-50500000, chr12: 50500000-51000000, chr12: 51000000-51500000,chr12: 53000000-53500000, chr12: 53500000-54000000, chr12:54000000-54500000, chr12: 55500000-56000000, chr12: 56000000-56500000,chr12: 57000000-57500000, chr12: 57500000-58000000, chr12:60500000-61000000, chr12: 61000000-61500000, chr12: 62000000-62500000,chr12: 64500000-65000000, chr12: 66000000-66500000, chr12:68000000-68500000, chr12: 73000000-73500000, chr12: 75500000-76000000,chr12: 76000000-76500000, chr12: 91500000-92000000, chr12:93000000-93500000, chr12: 93500000-94000000, chr12: 96000000-96500000,chr12: 98500000-99000000, chr12: 101500000-102000000, chr12:102500000-103000000, chr12: 104000000-104500000, chr12:104500000-105000000, chr12: 105000000-105500000, chr12:106500000-107000000, chr12: 108500000-109000000, chr12:109500000-110000000, chr12: 110000000-110500000, chr12:110500000-111000000, chr12: 111000000-111500000, chr12:112000000-112500000, chr12: 112500000-113000000, chr12:113000000-113500000, chr12: 116000000-116500000, chr12:116500000-117000000, chr12: 118000000-118500000, chr12:120000000-120500000, chr12: 120500000-121000000, chr12:121000000-121500000, chr12: 121500000-122000000, chr12:122000000-122500000, chr12: 123500000-124000000, chr12:127500000-128000000 13 chr13: 16000000-16500000, chr13:18000000-18500000, chr13: 18500000-19000000, chr13: 19000000-19500000,chr13: 21500000-22000000, chr13: 27000000-27500000, chr13:28000000-28500000, chr13: 30000000-30500000, chr13: 35500000-36000000,chr13: 36000000-36500000, chr13: 40000000-40500000, chr13:41000000-41500000, chr13: 44000000-44500000, chr13: 46000000-46500000,chr13: 49500000-50000000, chr13: 56500000-57000000, chr13:57000000-57500000, chr13: 60500000-61000000, chr13: 66500000-67000000,chr13: 73000000-73500000, chr13: 90500000-91000000, chr13:92500000-93000000, chr13: 97500000-98000000, chr13: 112000000-11250000014 chr14: 18000000-18500000, chr14: 18500000-19000000, chr14:19000000-19500000, chr14: 19500000-20000000, chr14: 21000000-21500000,chr14: 22500000-23000000, chr14: 23000000-23500000, chr14:25500000-26000000, chr14: 28000000-28500000, chr14: 30000000-30500000,chr14: 34500000-35000000, chr14: 35000000-35500000, chr14:39000000-39500000, chr14: 39500000-40000000, chr14: 43000000-43500000,chr14: 49500000-50000000, chr14: 50500000-51000000, chr14:51500000-52000000, chr14: 55000000-55500000, chr14: 55500000-56000000,chr14: 59000000-59500000, chr14: 60000000-60500000, chr14:64500000-65000000, chr14: 65000000-65500000, chr14: 70500000-71000000,chr14: 73000000-73500000, chr14: 74000000-74500000, chr14:75000000-75500000, chr14: 77000000-77500000, chr14: 86500000-87000000,chr14: 88500000-89000000, chr14: 89000000-89500000, chr14:91000000-91500000, chr14: 97000000-97500000, chr14: 97500000-98000000 15chr15: 17000000-17500000, chr15: 19500000-20000000, chr15:20000000-20500000, chr15: 20500000-21000000, chr15: 21000000-21500000,chr15: 21500000-22000000, chr15: 22000000-22500000, chr15:23000000-23500000, chr15: 24000000-24500000, chr15: 24500000-25000000,chr15: 26500000-27000000, chr15: 28500000-29000000, chr15:30000000-30500000, chr15: 30500000-31000000, chr15: 32000000-32500000,chr15: 34000000-34500000, chr15: 35000000-35500000, chr15:36000000-36500000, chr15: 41000000-41500000, chr15: 41500000-42000000,chr15: 43000000-43500000, chr15: 46000000-46500000, chr15:47000000-47500000, chr15: 48500000-49000000, chr15: 50000000-50500000,chr15: 53000000-53500000, chr15: 55000000-55500000, chr15:57000000-57500000, chr15: 58000000-58500000, chr15: 60000000-60500000,chr15: 63000000-63500000, chr15: 63500000-64000000, chr15:64000000-64500000, chr15: 64500000-65000000, chr15: 65500000-66000000,chr15: 69000000-69500000, chr15: 70000000-70500000, chr15:74500000-75000000, chr15: 81000000-81500000, chr15: 81500000-82000000,chr15: 82000000-82500000, chr15: 84000000-84500000, chr15:85500000-86000000, chr15: 90000000-90500000, chr15: 90500000-91000000,chr15: 91500000-92000000, chr15: 94000000-94500000 16 chr16:4500000-5000000, chr16: 8500000-9000000, chr16: 10500000-11000000,chr16: 11500000- 12000000, chr16: 14500000-15000000, chr16:15000000-15500000, chr16: 15500000-16000000, chr16: 17000000-17500000,chr16: 18000000-18500000, chr16: 22000000-22500000, chr16:23500000-24000000, chr16: 24000000-24500000, chr16: 24500000-25000000,chr16: 26500000-27000000, chr16: 27000000-27500000, chr16:29000000-29500000, chr16: 29500000-30000000, chr16: 30500000-31000000,chr16: 31000000-31500000, chr16: 32000000-32500000, chr16:32500000-33000000, chr16: 33000000-33500000, chr16: 33500000-34000000,chr16: 34000000-34500000, chr16: 34500000-35000000, chr16:35000000-35500000, chr16: 46000000-46500000, chr16: 53000000-53500000,chr16: 53500000-54000000, chr16: 54000000-54500000, chr16:57000000-57500000, chr16: 67500000-68000000, chr16: 68000000-68500000,chr16: 69000000-69500000, chr16: 71500000-72000000, chr16:72000000-72500000, chr16: 74500000-75000000, chr16: 79000000-79500000,chr16: 81000000-81500000, chr16: 81500000-82000000, chr16:84500000-85000000, chr16: 90000000-90338345 17 chr17: 0-500000, chr17:1000000-1500000, chr17: 1500000-2000000, chr17: 2000000-2500000, chr17:2500000-3000000, chr17: 4000000-4500000, chr17: 4500000-5000000, chr17:5000000- 5500000, chr17: 7000000-7500000, chr17: 7500000-8000000, chr17:8000000-8500000, chr17: 8500000-9000000, chr17: 14000000-14500000,chr17: 16000000-16500000, chr17: 19000000-19500000, chr17:19500000-20000000, chr17: 20500000-21000000, chr17: 21000000-21500000,chr17: 21500000-22000000, chr17: 22000000-22500000, chr17:22500000-23000000, chr17: 26500000-27000000, chr17: 28500000-29000000,chr17: 30000000-30500000, chr17: 31000000-31500000, chr17:35000000-35500000, chr17: 35500000-36000000, chr17: 36000000-36500000,chr17: 36500000-37000000, chr17: 37000000-37500000, chr17:38000000-38500000, chr17: 38500000-39000000, chr17: 39000000-39500000,chr17: 39500000-40000000, chr17: 40000000-40500000, chr17:42000000-42500000, chr17: 42500000-43000000, chr17: 43500000-44000000,chr17: 44000000-44500000, chr17: 44500000-45000000, chr17:45000000-45500000, chr17: 47500000-48000000, chr17: 48500000-49000000,chr17: 49000000-49500000, chr17: 49500000-50000000, chr17:50000000-50500000, chr17: 50500000-51000000, chr17: 54000000-54500000,chr17: 56500000-57000000, chr17: 57000000-57500000, chr17:58000000-58500000, chr17: 59500000-60000000, chr17: 62500000-63000000,chr17: 63500000-64000000, chr17: 64000000-64500000, chr17:65000000-65500000, chr17: 66000000-66500000, chr17: 67000000-67500000,chr17: 68000000-68500000, chr17: 73500000-74000000, chr17:74500000-75000000, chr17: 75000000-75500000, chr17: 75500000-76000000,chr17: 76000000-76500000, chr17: 77000000-77500000, chr17:78500000-79000000, chr17: 79500000-80000000, chr17: 80000000-80500000 18chr18: 3000000-3500000, chr18: 5500000-6000000, chr18: 6500000-7000000,chr18: 11000000- 11500000, chr18: 14000000-14500000, chr18:14500000-15000000, chr18: 15000000-15500000, chr18: 21000000-21500000,chr18: 23500000-24000000, chr18: 27500000-28000000, chr18:35000000-35500000, chr18: 46000000-46500000, chr18: 51000000-51500000,chr18: 61000000-61500000, chr18: 78000000-78500000 19 chr19: 0-500000,chr19: 500000-1000000, chr19: 1500000-2000000, chr19: 2000000-2500000,chr19: 2500000-3000000, chr19: 3000000-3500000, chr19: 4000000-4500000,chr19: 4500000- 5000000, chr19: 5500000-6000000, chr19: 6000000-6500000,chr19: 6500000-7000000, chr19: 7000000-7500000, chr19: 7500000-8000000,chr19: 8000000-8500000, chr19: 9500000- 10000000, chr19:10000000-10500000, chr19: 10500000-11000000, chr19: 11000000-11500000,chr19: 11500000-12000000, chr19: 12500000-13000000, chr19:13000000-13500000, chr19: 13500000-14000000, chr19: 14000000-14500000,chr19: 14500000-15000000, chr19: 15500000-16000000, chr19:16000000-16500000, chr19: 16500000-17000000, chr19: 17000000-17500000,chr19: 17500000-18000000, chr19: 18000000-18500000, chr19:18500000-19000000, chr19: 19000000-19500000, chr19: 20500000-21000000,chr19: 22000000-22500000, chr19: 22500000-23000000, chr19:27500000-28000000, chr19: 34000000-34500000, chr19: 35000000-35500000,chr19: 35500000-36000000, chr19: 38000000-38500000, chr19:38500000-39000000, chr19: 39000000-39500000, chr19: 39500000-40000000,chr19: 40000000-40500000, chr19: 40500000-41000000, chr19:41000000-41500000, chr19: 41500000-42000000, chr19: 42000000-42500000,chr19: 42500000-43000000, chr19: 43500000-44000000, chr19:44500000-45000000, chr19: 45000000-45500000, chr19: 45500000-46000000,chr19: 46500000-47000000, chr19: 47000000-47500000, chr19:48000000-48500000, chr19: 48500000-49000000, chr19: 49000000-49500000,chr19: 49500000-50000000, chr19: 50500000-51000000, chr19:51000000-51500000, chr19: 51500000-52000000, chr19: 54000000-54500000,chr19: 55500000-56000000 20 chr20: 1000000-1500000, chr20:1500000-2000000, chr20: 2500000-3000000, chr20: 3000000- 3500000, chr20:3500000-4000000, chr20: 4500000-5000000, chr20: 5000000-5500000, chr20:5500000-6000000, chr20: 8000000-8500000, chr20: 21500000-22000000,chr20: 25500000- 26000000, chr20: 26000000-26500000, chr20:28500000-29000000, chr20: 29000000-29500000, chr20: 29500000-30000000,chr20: 30000000-30500000, chr20: 30500000-31000000, chr20:31500000-32000000, chr20: 32000000-32500000, chr20: 33000000-33500000,chr20: 33500000-34000000, chr20: 34000000-34500000, chr20:34500000-35000000, chr20: 36500000-37000000, chr20: 37000000-37500000,chr20: 38000000-38500000, chr20: 38500000-39000000, chr20:40500000-41000000, chr20: 43500000-44000000, chr20: 44000000-44500000,chr20: 44500000-45000000, chr20: 45000000-45500000, chr20:45500000-46000000, chr20: 46000000-46500000, chr20: 47000000-47500000,chr20: 48500000-49000000, chr20: 49500000-50000000, chr20:50000000-50500000, chr20: 51500000-52000000, chr20: 52000000-52500000,chr20: 53500000-54000000, chr20: 57000000-57500000, chr20:62500000-63000000, chr20: 63000000-63500000 21 chr21: 5000000-5500000,chr21: 5500000-6000000, chr21: 6000000-6500000, chr21: 6500000- 7000000,chr21: 7000000-7500000, chr21: 7500000-8000000, chr21: 8000000-8500000,chr21: 8500000-9000000, chr21: 9000000-9500000, chr21: 9500000-10000000,chr21: 10000000- 10500000, chr21: 10500000-11000000, chr21:13000000-13500000, chr21: 13500000-14000000, chr21: 17000000-17500000,chr21: 25500000-26000000, chr21: 29000000-29500000, chr21:31000000-31500000, chr21: 33000000-33500000, chr21: 34500000-35000000,chr21: 36000000-36500000, chr21: 40000000-40500000, chr21:42000000-42500000 22 chr22: 10500000-11000000, chr22: 11000000-11500000,chr22: 11500000-12000000, chr22: 12000000-12500000, chr22:12500000-13000000, chr22: 15000000-15500000, chr22: 15500000-16000000,chr22: 16000000-16500000, chr22: 16500000-17000000, chr22:18000000-18500000, chr22: 18500000-19000000, chr22: 21000000-21500000,chr22: 21500000-22000000, chr22: 27000000-27500000, chr22:29500000-30000000, chr22: 30000000-30500000, chr22: 31000000-31500000,chr22: 31500000-32000000, chr22: 35000000-35500000, chr22:35500000-36000000, chr22: 36000000-36500000, chr22: 36500000-37000000,chr22: 37000000-37500000, chr22: 37500000-38000000, chr22:38000000-38500000, chr22: 40000000-40500000, chr22: 40500000-41000000,chr22: 41000000-41500000, chr22: 41500000-42000000, chr22:48500000-49000000

TABLE 17 1 chr1: 500000-1000000, chr1: 1500000-2000000, chr1:2500000-3000000, chr1: 8000000-8500000, chr1: 10000000-10500000, chr1:12500000-13000000, chr1: 13000000-13500000, chr1: 16000000- 16500000,chr1: 16500000-17000000, chr1: 18000000-18500000, chr1:19000000-19500000, chr1: 20500000-21000000, chr1: 21000000-21500000,chr1: 23000000-23500000, chr1: 23500000- 24000000, chr1:26000000-26500000, chr1: 26500000-27000000, chr1: 27000000-27500000,chr1: 27500000-28000000, chr1: 28000000-28500000, chr1:31500000-32000000, chr1: 32000000- 32500000, chr1: 35500000-36000000,chr1: 40000000-40500000, chr1: 41000000-41500000, chr1:44500000-45000000, chr1: 45500000-46000000, chr1: 48000000-48500000,chr1: 50000000- 50500000, chr1: 51500000-52000000, chr1:52500000-53000000, chr1: 61000000-61500000, chr1: 63500000-64000000,chr1: 64500000-65000000, chr1: 65000000-65500000, chr1: 66500000-67000000, chr1: 67000000-67500000, chr1: 83000000-83500000, chr1:84000000-84500000, chr1: 88500000-89000000, chr1: 91500000-92000000,chr1: 92500000-93000000, chr1: 94500000- 95000000, chr1:97500000-98000000, chr1: 98000000-98500000, chr1: 98500000-99000000,chr1: 107500000-108000000, chr1: 108500000-109000000, chr1:111500000-112000000, chr1: 112500000-113000000, chr1:116000000-116500000, chr1: 116500000-117000000, chr1:120000000-120500000, chr1: 120500000-121000000, chr1:121000000-121500000, chr1: 125000000-125500000, chr1:143000000-143500000, chr1: 143500000-144000000, chr1:144000000-144500000, chr1: 144500000-145000000, chr1:145000000-145500000, chr1: 146000000-146500000, chr1:146500000-147000000, chr1: 147500000-148000000, chr1:148000000-148500000, chr1: 148500000-149000000, chr1:149000000-149500000, chr1: 150000000-150500000, chr1:150500000-151000000, chr1: 151000000-151500000, chr1:151500000-152000000, chr1: 153500000-154000000, chr1:154000000-154500000, chr1: 154500000-155000000, chr1:156000000-156500000, chr1: 156500000-157000000, chr1:157000000-157500000, chr1: 159000000-159500000, chr1:160000000-160500000, chr1: 161000000-161500000, chr1:161500000-162000000, chr1: 165500000-166000000, chr1:167500000-168000000, chr1: 168500000-169000000, chr1:169500000-170000000, chr1: 171000000-171500000, chr1:171500000-172000000, chr1: 172500000-173000000, chr1:173500000-174000000, chr1: 174000000-174500000, chr1:176500000-177000000, chr1: 177500000-178000000, chr1:181000000-181500000, chr1: 182500000-183000000, chr1:183000000-183500000, chr1: 185000000-185500000, chr1:193000000-193500000, chr1: 197000000-197500000, chr1:198500000-199000000, chr1: 199000000-199500000, chr1:200000000-200500000, chr1: 203000000-203500000, chr1:204000000-204500000, chr1: 206500000-207000000, chr1:210000000-210500000, chr1: 213500000-214000000, chr1:220000000-220500000, chr1: 222500000-223000000, chr1:227000000-227500000, chr1: 233000000-233500000, chr1:233500000-234000000, chr1: 235000000-235500000, chr1:235500000-236000000, chr1: 236000000-236500000, chr1:243500000-244000000, chr1: 246500000-247000000, chr1:247000000-247500000 2 chr2: 1500000-2000000, chr2: 8500000-9000000,chr2: 20000000-20500000, chr2: 21000000- 21500000, chr2:24500000-25000000, chr2: 25000000-25500000, chr2: 27500000-28000000,chr2: 36000000-36500000, chr2: 36500000-37000000, chr2:37000000-37500000, chr2: 37500000- 38000000, chr2: 39000000-39500000,chr2: 42000000-42500000, chr2: 43000000-43500000, chr2:45500000-46000000, chr2: 47000000-47500000, chr2: 48000000-48500000,chr2: 50000000- 50500000, chr2: 61500000-62000000, chr2:68500000-69000000, chr2: 69500000-70000000, chr2: 72500000-73000000,chr2: 75000000-75500000, chr2: 80000000-80500000, chr2: 84500000-85000000, chr2: 87000000-87500000, chr2: 87500000-88000000, chr2:89500000-90000000, chr2: 90000000-90500000, chr2: 91000000-91500000,chr2: 91500000-92000000, chr2: 92000000- 92500000, chr2:94500000-95000000, chr2: 95500000-96000000, chr2: 98500000-99000000,chr2: 102000000-102500000, chr2: 107000000-107500000, chr2:109500000-110000000, chr2: 112500000-113000000, chr2:113000000-113500000, chr2: 113500000-114000000, chr2:119500000-120000000, chr2: 129000000-129500000, chr2:130000000-130500000, chr2: 131500000-132000000, chr2:132000000-132500000, chr2: 132500000-133000000, chr2:134000000-134500000, chr2: 135500000-136000000, chr2:136000000-136500000, chr2: 139500000-140000000, chr2:143000000-143500000, chr2: 143500000-144000000, chr2:144500000-145000000, chr2: 148500000-149000000, chr2:156000000-156500000, chr2: 157000000-157500000, chr2:158000000-158500000, chr2: 174500000-175000000, chr2:177000000-177500000, chr2: 178000000-178500000, chr2:181000000-181500000, chr2: 181500000-182000000, chr2:189000000-189500000, chr2: 189500000-190000000, chr2:190000000-190500000, chr2: 190500000-191000000, chr2:191000000-191500000, chr2: 191500000-192000000, chr2:196000000-196500000, chr2: 197000000-197500000, chr2:200500000-201000000, chr2: 201000000-201500000, chr2:201500000-202000000, chr2: 203000000-203500000, chr2:203500000-204000000, chr2: 207500000-208000000, chr2:208500000-209000000, chr2: 210000000-210500000, chr2:216000000-216500000, chr2: 218000000-218500000, chr2:224500000-225000000, chr2: 235000000-235500000, chr2:235500000-236000000, chr2: 240500000-241000000 3 chr3: 2500000-3000000,chr3: 3000000-3500000, chr3: 4500000-5000000, chr3: 10000000- 10500000,chr3: 12500000-13000000, chr3: 14000000-14500000, chr3:17000000-17500000, chr3: 17500000-18000000, chr3: 26000000-26500000,chr3: 27500000-28000000, chr3: 28500000- 29000000, chr3:30500000-31000000, chr3: 32000000-32500000, chr3: 33500000-34000000,chr3: 36000000-36500000, chr3: 38000000-38500000, chr3:39000000-39500000, chr3: 47000000- 47500000, chr3: 47500000-48000000,chr3: 48500000-49000000, chr3: 54500000-55000000, chr3:55500000-56000000, chr3: 56500000-57000000, chr3: 57500000-58000000,chr3: 59000000- 59500000, chr3: 64500000-65000000, chr3:70000000-70500000, chr3: 71000000-71500000, chr3: 75000000-75500000,chr3: 75500000-76000000, chr3: 88000000-88500000, chr3: 91000000-91500000, chr3: 100000000-100500000, chr3: 101000000-101500000, chr3:101500000- 102000000, chr3: 105500000-106000000, chr3:106000000-106500000, chr3: 107500000- 108000000, chr3:112500000-113000000, chr3: 122000000-122500000, chr3: 125000000-125500000, chr3: 125500000-126000000, chr3: 127000000-127500000, chr3:129500000- 130000000, chr3: 134000000-134500000, chr3:135500000-136000000, chr3: 136500000- 137000000, chr3:143000000-143500000, chr3: 150000000-150500000, chr3: 151000000-151500000, chr3: 151500000-152000000, chr3: 152000000-152500000, chr3:153000000- 153500000, chr3: 156500000-157000000, chr3:157000000-157500000, chr3: 158500000- 159000000, chr3:160500000-161000000, chr3: 161000000-161500000, chr3: 165500000-166000000, chr3: 169000000-169500000, chr3: 170000000-170500000, chr3:171000000- 171500000, chr3: 172000000-172500000, chr3:179000000-179500000, chr3: 182500000- 183000000, chr3:184500000-185000000, chr3: 186500000-187000000, chr3: 198000000-198295559 4 chr4: 5500000-6000000, chr4: 8500000-9000000, chr4:9000000-9500000, chr4: 18000000- 18500000, chr4: 21000000-21500000,chr4: 26500000-27000000, chr4: 36000000-36500000, chr4:38500000-39000000, chr4: 39000000-39500000, chr4: 39500000-40000000,chr4: 40000000- 40500000, chr4: 48500000-49000000, chr4:49000000-49500000, chr4: 49500000-50000000, chr4: 54500000-55000000,chr4: 69500000-70000000, chr4: 70500000-71000000, chr4: 71500000-72000000, chr4: 75500000-76000000, chr4: 77500000-78000000, chr4:78500000-79000000, chr4: 81500000-82000000, chr4: 82000000-82500000,chr4: 83000000-83500000, chr4: 89500000- 90000000, chr4:98000000-98500000, chr4: 99500000-100000000, chr4: 107500000-108000000,chr4: 109500000-110000000, chr4: 113500000-114000000, chr4:128500000-129000000, chr4: 139000000-139500000, chr4:142500000-143000000, chr4: 150500000-151000000, chr4:152000000-152500000, chr4: 152500000-153000000, chr4:153000000-153500000, chr4: 153500000-154000000, chr4:158500000-159000000, chr4: 159000000-159500000, chr4:173000000-173500000, chr4: 176000000-176500000, chr4:181500000-182000000, chr4: 189500000-190000000, chr4:190000000-190214555 5 chr5: 9000000-9500000, chr5: 9500000-10000000,chr5: 14000000-14500000, chr5: 15500000- 16000000, chr5:17500000-18000000, chr5: 21000000-21500000, chr5: 23500000-24000000,chr5: 34000000-34500000, chr5: 39000000-39500000, chr5:50500000-51000000, chr5: 51000000- 51500000, chr5: 54500000-55000000,chr5: 56000000-56500000, chr5: 56500000-57000000, chr5:59000000-59500000, chr5: 59500000-60000000, chr5: 62000000-62500000,chr5: 65500000- 66000000, chr5: 68000000-68500000, chr5:69000000-69500000, chr5: 69500000-70000000, chr5: 70000000-70500000,chr5: 70500000-71000000, chr5: 71000000-71500000, chr5: 75000000-75500000, chr5: 75500000-76000000, chr5: 80000000-80500000, chr5:85000000-85500000, chr5: 87000000-87500000, chr5: 91000000-91500000,chr5: 94500000-95000000, chr5: 96000000- 96500000, chr5:96500000-97000000, chr5: 109500000-110000000, chr5: 111000000-111500000,chr5: 112000000-112500000, chr5: 112500000-113000000, chr5:114000000-114500000, chr5: 115500000-116000000, chr5:119000000-119500000, chr5: 124500000-125000000, chr5:126500000-127000000, chr5: 131000000-131500000, chr5:138000000-138500000, chr5: 140000000-140500000, chr5:140500000-141000000, chr5: 142000000-142500000, chr5:142500000-143000000, chr5: 143000000-143500000, chr5:145000000-145500000, chr5: 146000000-146500000, chr5:157500000-158000000, chr5: 159000000-159500000, chr5:167500000-168000000, chr5: 169000000-169500000, chr5:172000000-172500000, chr5: 177000000-177500000 6 chr6:11000000-11500000, chr6: 13500000-14000000, chr6: 14500000-15000000,chr6: 15000000- 15500000, chr6: 16500000-17000000, chr6:17500000-18000000, chr6: 25500000-26000000, chr6: 26000000-26500000,chr6: 29500000-30000000, chr6: 30000000-30500000, chr6: 30500000-31000000, chr6: 31000000-31500000, chr6: 31500000-32000000, chr6:32000000-32500000, chr6: 32500000-33000000, chr6: 33000000-33500000,chr6: 33500000-34000000, chr6: 36000000- 36500000, chr6:36500000-37000000, chr6: 38500000-39000000, chr6: 41000000-41500000,chr6: 41500000-42000000, chr6: 42000000-42500000, chr6:42500000-43000000, chr6: 43000000- 43500000, chr6: 44000000-44500000,chr6: 45000000-45500000, chr6: 53000000-53500000, chr6:57500000-58000000, chr6: 58000000-58500000, chr6: 60000000-60500000,chr6: 60500000- 61000000, chr6: 61000000-61500000, chr6:63500000-64000000, chr6: 73000000-73500000, chr6: 87000000-87500000,chr6: 87500000-88000000, chr6: 89500000-90000000, chr6: 90500000-91000000, chr6: 105000000-105500000, chr6: 106000000-106500000, chr6:108500000- 109000000, chr6: 110500000-111000000, chr6:111500000-112000000, chr6: 116000000- 116500000, chr6:118500000-119000000, chr6: 119000000-119500000, chr6: 119500000-120000000, chr6: 127500000-128000000, chr6: 128000000-128500000, chr6:129000000- 129500000, chr6: 129500000-130000000, chr6:131000000-131500000, chr6: 135000000- 135500000, chr6:135500000-136000000, chr6: 137000000-137500000, chr6: 137500000-138000000, chr6: 139000000-139500000, chr6: 142000000-142500000, chr6:142500000- 143000000, chr6: 143500000-144000000, chr6:144500000-145000000, chr6: 149000000- 149500000, chr6:149500000-150000000, chr6: 154000000-154500000, chr6: 156500000-157000000, chr6: 157000000-157500000, chr6: 158500000-159000000, chr6:166500000- 167000000, chr6: 167500000-168000000 7 chr7: 1000000-1500000,chr7: 3000000-3500000, chr7: 6000000-6500000, chr7: 6500000-7000000,chr7: 7000000-7500000, chr7: 7500000-8000000, chr7: 12000000-12500000,chr7: 12500000- 13000000, chr7: 17000000-17500000, chr7:18000000-18500000, chr7: 21000000-21500000, chr7: 36500000-37000000,chr7: 37000000-37500000, chr7: 37500000-38000000, chr7: 38000000-38500000, chr7: 38500000-39000000, chr7: 40000000-40500000, chr7:45500000-46000000, chr7: 51000000-51500000, chr7: 51500000-52000000,chr7: 56500000-57000000, chr7: 57500000- 58000000, chr7:58000000-58500000, chr7: 63000000-63500000, chr7: 63500000-64000000,chr7: 71500000-72000000, chr7: 72000000-72500000, chr7:72500000-73000000, chr7: 76500000- 77000000, chr7: 77500000-78000000,chr7: 91000000-91500000, chr7: 92500000-93000000, chr7:93500000-94000000, chr7: 98000000-98500000, chr7: 100000000-100500000,chr7: 100500000-101000000, chr7: 102500000-103000000, chr7:103000000-103500000, chr7: 105000000-105500000, chr7:106000000-106500000, chr7: 107000000-107500000, chr7:115000000-115500000, chr7: 127500000-128000000, chr7:130000000-130500000, chr7: 130500000-131000000, chr7:133000000-133500000, chr7: 133500000-134000000, chr7:135500000-136000000, chr7: 139000000-139500000, chr7:141500000-142000000, chr7: 142500000-143000000, chr7:143000000-143500000, chr7: 144500000-145000000, chr7:154000000-154500000 8 chr8: 3000000-3500000, chr8: 6500000-7000000,chr8: 7000000-7500000, chr8: 7500000-8000000, chr8: 8000000-8500000,chr8: 8500000-9000000, chr8: 12000000-12500000, chr8: 12500000-13000000, chr8: 17500000-18000000, chr8: 27000000-27500000, chr8:29000000-29500000, chr8: 30000000-30500000, chr8: 30500000-31000000,chr8: 33000000-33500000, chr8: 35500000- 36000000, chr8:37500000-38000000, chr8: 55000000-55500000, chr8: 60500000-61000000,chr8: 61000000-61500000, chr8: 65500000-66000000, chr8:66500000-67000000, chr8: 69000000- 69500000, chr8: 80500000-81000000,chr8: 81500000-82000000, chr8: 84000000-84500000, chr8:85500000-86000000, chr8: 86000000-86500000, chr8: 91000000-91500000,chr8: 91500000- 92000000, chr8: 97000000-97500000, chr8:100000000-100500000, chr8: 120500000-121000000, chr8:124000000-124500000, chr8: 125000000-125500000, chr8:129500000-130000000, chr8: 130500000-131000000, chr8:135000000-135500000, chr8: 135500000-136000000, chr8:137500000-138000000, chr8: 139500000-140000000, chr8:140500000-141000000 9 chr9: 0-500000, chr9: 2500000-3000000, chr9:6500000-7000000, chr9: 8000000-8500000, chr9: 13500000-14000000, chr9:15000000-15500000, chr9: 17500000-18000000, chr9: 21500000- 22000000,chr9: 22000000-22500000, chr9: 28000000-28500000, chr9:32000000-32500000, chr9: 33000000-33500000, chr9: 34000000-34500000,chr9: 35500000-36000000, chr9: 36000000- 36500000, chr9:39000000-39500000, chr9: 39500000-40000000, chr9: 40000000-40500000,chr9: 40500000-41000000, chr9: 41000000-41500000, chr9:41500000-42000000, chr9: 42000000- 42500000, chr9: 42500000-43000000,chr9: 60500000-61000000, chr9: 61000000-61500000, chr9:61500000-62000000, chr9: 62000000-62500000, chr9: 62500000-63000000,chr9: 63000000- 63500000, chr9: 63500000-64000000, chr9:64000000-64500000, chr9: 64500000-65000000, chr9: 65000000-65500000,chr9: 65500000-66000000, chr9: 66000000-66500000, chr9: 66500000-67000000, chr9: 67000000-67500000, chr9: 67500000-68000000, chr9:71500000-72000000, chr9: 72000000-72500000, chr9: 73500000-74000000,chr9: 75500000-76000000, chr9: 77500000- 78000000, chr9:78500000-79000000, chr9: 80500000-81000000, chr9: 85000000-85500000,chr9: 89000000-89500000, chr9: 89500000-90000000, chr9:92500000-93000000, chr9: 97500000- 98000000, chr9: 98000000-98500000,chr9: 105000000-105500000, chr9: 107500000-108000000, chr9:112000000-112500000, chr9: 125500000-126000000, chr9:126000000-126500000, chr9: 128000000-128500000, chr9:129500000-130000000, chr9: 132000000-132500000, chr9:135000000-135500000 10 chr10: 3500000-4000000, chr10: 6000000-6500000,chr10: 7500000-8000000, chr10: 8000000- 8500000, chr10: 8500000-9000000,chr10: 9000000-9500000, chr10: 12000000-12500000, chr10:14500000-15000000, chr10: 17000000-17500000, chr10: 21500000-22000000,chr10: 24000000-24500000, chr10: 27000000-27500000, chr10:28000000-28500000, chr10: 32000000-32500000, chr10: 35000000-35500000,chr10: 36500000-37000000, chr10: 37000000-37500000, chr10:38000000-38500000, chr10: 38500000-39000000, chr10: 42000000-42500000,chr10: 44000000-44500000, chr10: 46500000-47000000, chr10:47500000-48000000, chr10: 49000000-49500000, chr10: 53500000-54000000,chr10: 58000000-58500000, chr10: 59000000-59500000, chr10:62000000-62500000, chr10: 62500000-63000000, chr10: 63000000-63500000,chr10: 68000000-68500000, chr10: 68500000-69000000, chr10:69500000-70000000, chr10: 72000000-72500000, chr10: 73000000-73500000,chr10: 82000000-82500000, chr10: 87500000-88000000, chr10:88500000-89000000, chr10: 89500000-90000000, chr10: 92500000-93000000,chr10: 94500000-95000000, chr10: 95500000-96000000, chr10:97000000-97500000, chr10: 100000000-100500000, chr10:101000000-101500000, chr10: 101500000-102000000, chr10:102000000-102500000, chr10: 102500000-103000000, chr10:104000000-104500000, chr10: 107000000-107500000, chr10:108000000-108500000, chr10: 109000000-109500000, chr10:109500000-110000000, chr10: 110500000-111000000, chr10:111500000-112000000, chr10: 116000000-116500000, chr10:122000000-122500000, chr10: 123500000-124000000, chr10:127000000-127500000, chr10: 128500000-129000000, chr10:129500000-130000000, chr10: 133500000-133797422 11 chr11: 0-500000,chr11: 3500000-4000000, chr11: 6500000-7000000, chr11:11500000-12000000, chr11: 12000000-12500000, chr11: 18000000-18500000,chr11: 33000000-33500000, chr11: 34500000-35000000, chr11:39500000-40000000, chr11: 46000000-46500000, chr11: 47500000-48000000,chr11: 48500000-49000000, chr11: 49000000-49500000, chr11:49500000-50000000, chr11: 50000000-50500000, chr11: 58500000-59000000,chr11: 61000000-61500000, chr11: 62000000-62500000, chr11:62500000-63000000, chr11: 64500000-65000000, chr11: 65000000-65500000,chr11: 65500000-66000000, chr11: 66000000-66500000, chr11:67000000-67500000, chr11: 72000000-72500000, chr11: 72500000-73000000,chr11: 73000000-73500000, chr11: 76000000-76500000, chr11:77500000-78000000, chr11: 78000000-78500000, chr11: 80500000-81000000,chr11: 86000000-86500000, chr11: 88000000-88500000, chr11:89500000-90000000, chr11: 92000000-92500000, chr11: 92500000-93000000,chr11: 95000000-95500000, chr11: 95500000-96000000, chr11:100000000-100500000, chr11: 102000000-102500000, chr11:103000000-103500000, chr11: 107500000-108000000, chr11:111500000-112000000, chr11: 114000000-114500000, chr11:116000000-116500000, chr11: 117000000-117500000, chr11:118500000-119000000, chr11: 119000000-119500000, chr11:121000000-121500000, chr11: 128500000-129000000, chr11:133500000-134000000 12 chr12: 500000-1000000, chr12: 6500000-7000000,chr12: 8500000-9000000, chr12: 9500000- 10000000, chr12:12000000-12500000, chr12: 12500000-13000000, chr12: 14500000-15000000,chr12: 15500000-16000000, chr12: 21500000-22000000, chr12:22000000-22500000, chr12: 23500000-24000000, chr12: 24500000-25000000,chr12: 25000000-25500000, chr12: 25500000-26000000, chr12:30000000-30500000, chr12: 31500000-32000000, chr12: 34500000-35000000,chr12: 40000000-40500000, chr12: 47000000-47500000, chr12:48500000-49000000, chr12: 49500000-50000000, chr12: 50000000-50500000,chr12: 53000000-53500000, chr12: 53500000-54000000, chr12:54000000-54500000, chr12: 54500000-55000000, chr12: 55500000-56000000,chr12: 56000000-56500000, chr12: 57000000-57500000, chr12:57500000-58000000, chr12: 62000000-62500000, chr12: 64500000-65000000,chr12: 65000000-65500000, chr12: 66000000-66500000, chr12:68000000-68500000, chr12: 71500000-72000000, chr12: 75000000-75500000,chr12: 75500000-76000000, chr12: 76000000-76500000, chr12:89500000-90000000, chr12: 91000000-91500000, chr12: 91500000-92000000,chr12: 96000000-96500000, chr12: 98500000-99000000, chr12:101500000-102000000, chr12: 105000000-105500000, chr12:107000000-107500000, chr12: 108500000-109000000, chr12:110000000-110500000, chr12: 110500000-111000000, chr12:111000000-111500000, chr12: 111500000-112000000, chr12:112000000-112500000, chr12: 112500000-113000000, chr12:113000000-113500000, chr12: 116000000-116500000, chr12:116500000-117000000, chr12: 118000000-118500000, chr12:120000000-120500000, chr12: 121500000-122000000, chr12:122000000-122500000, chr12: 123000000-123500000, chr12:127500000-128000000 13 chr13: 18000000-18500000, chr13:18500000-19000000, chr13: 19000000-19500000, chr13: 21500000-22000000,chr13: 22000000-22500000, chr13: 27000000-27500000, chr13:28000000-28500000, chr13: 32500000-33000000, chr13: 35500000-36000000,chr13: 36000000-36500000, chr13: 40000000-40500000, chr13:41000000-41500000, chr13: 42000000-42500000, chr13: 45000000-45500000,chr13: 48000000-48500000, chr13: 49500000-50000000, chr13:73500000-74000000, chr13: 74000000-74500000, chr13: 100000000-100500000,chr13: 106000000-106500000, chr13: 108000000-108500000 14 chr14:18000000-18500000, chr14: 18500000-19000000, chr14: 19000000-19500000,chr14: 21000000-21500000, chr14: 22500000-23000000, chr14:25500000-26000000, chr14: 31500000-32000000, chr14: 34500000-35000000,chr14: 35000000-35500000, chr14: 39500000-40000000, chr14:49500000-50000000, chr14: 50500000-51000000, chr14: 55000000-55500000,chr14: 60000000-60500000, chr14: 66000000-66500000, chr14:70500000-71000000, chr14: 71000000-71500000, chr14: 74000000-74500000,chr14: 75000000-75500000, chr14: 77000000-77500000, chr14:80500000-81000000, chr14: 84000000-84500000, chr14: 86500000-87000000,chr14: 88500000-89000000, chr14: 89500000-90000000, chr14:91000000-91500000, chr14: 106500000-107000000 15 chr15:17000000-17500000, chr15: 19500000-20000000, chr15: 20000000-20500000,chr15: 20500000-21000000, chr15: 21000000-21500000, chr15:21500000-22000000, chr15: 23000000-23500000, chr15: 23500000-24000000,chr15: 24000000-24500000, chr15: 28500000-29000000, chr15:30000000-30500000, chr15: 30500000-31000000, chr15: 32000000-32500000,chr15: 34000000-34500000, chr15: 35000000-35500000, chr15:36500000-37000000, chr15: 41000000-41500000, chr15: 43000000-43500000,chr15: 45500000-46000000, chr15: 46000000-46500000, chr15:47000000-47500000, chr15: 50000000-50500000, chr15: 51500000-52000000,chr15: 53000000-53500000, chr15: 60500000-61000000, chr15:61500000-62000000, chr15: 64500000-65000000, chr15: 65500000-66000000,chr15: 72000000-72500000, chr15: 73000000-73500000, chr15:81500000-82000000, chr15: 84000000-84500000, chr15: 85500000-86000000,chr15: 88000000-88500000, chr15: 90000000-90500000, chr15:90500000-91000000, chr15: 91000000-91500000, chr15: 92500000-93000000,chr15: 94000000-94500000, chr15: 100000000-100500000 16 chr16:3000000-3500000, chr16: 5000000-5500000, chr16: 8500000-9000000, chr16:11500000- 12000000, chr16: 15000000-15500000, chr16: 15500000-16000000,chr16: 16000000-16500000, chr16: 18000000-18500000, chr16:23000000-23500000, chr16: 23500000-24000000, chr16: 24500000-25000000,chr16: 27500000-28000000, chr16: 29000000-29500000, chr16:29500000-30000000, chr16: 30500000-31000000, chr16: 32000000-32500000,chr16: 32500000-33000000, chr16: 33000000-33500000, chr16:33500000-34000000, chr16: 34000000-34500000, chr16: 34500000-35000000,chr16: 35000000-35500000, chr16: 46000000-46500000, chr16:51000000-51500000, chr16: 52000000-52500000, chr16: 54000000-54500000,chr16: 57000000-57500000, chr16: 57500000-58000000, chr16:67500000-68000000, chr16: 72000000-72500000, chr16: 74500000-75000000,chr16: 81000000-81500000, chr16: 83500000-84000000, chr16:90000000-90338345 17 chr17: 0-500000, chr17: 1000000-1500000, chr17:2000000-2500000, chr17: 2500000-3000000, chr17: 4000000-4500000, chr17:4500000-5000000, chr17: 5000000-5500000, chr17: 7000000- 7500000, chr17:7500000-8000000, chr17: 8000000-8500000, chr17: 8500000-9000000, chr17:11500000-12000000, chr17: 16000000-16500000, chr17: 19000000-19500000,chr17: 19500000-20000000, chr17: 20000000-20500000, chr17:21500000-22000000, chr17: 22000000-22500000, chr17: 22500000-23000000,chr17: 26500000-27000000, chr17: 28500000-29000000, chr17:29000000-29500000, chr17: 31000000-31500000, chr17: 34500000-35000000,chr17: 35000000-35500000, chr17: 37000000-37500000, chr17:38500000-39000000, chr17: 39000000-39500000, chr17: 39500000-40000000,chr17: 40000000-40500000, chr17: 40500000-41000000, chr17:42000000-42500000, chr17: 43500000-44000000, chr17: 44000000-44500000,chr17: 44500000-45000000, chr17: 47500000-48000000, chr17:48000000-48500000, chr17: 48500000-49000000, chr17: 49000000-49500000,chr17: 50000000-50500000, chr17: 50500000-51000000, chr17:59500000-60000000, chr17: 61500000-62000000, chr17: 63500000-64000000,chr17: 64000000-64500000, chr17: 65000000-65500000, chr17:65500000-66000000, chr17: 66000000-66500000, chr17: 68000000-68500000,chr17: 69000000-69500000, chr17: 71500000-72000000, chr17:74500000-75000000, chr17: 75000000-75500000, chr17: 76000000-76500000,chr17: 76500000-77000000 18 chr18: 3000000-3500000, chr18:5500000-6000000, chr18: 7000000-7500000, chr18: 11000000- 11500000,chr18: 12500000-13000000, chr18: 14000000-14500000, chr18:15000000-15500000, chr18: 21000000-21500000, chr18: 24000000-24500000,chr18: 31500000-32000000, chr18: 35000000-35500000, chr18:42000000-42500000, chr18: 48500000-49000000, chr18: 73000000-73500000,chr18: 78000000-78500000 19 chr19: 0-500000, chr19: 1000000-1500000,chr19: 2000000-2500000, chr19: 3000000-3500000, chr19: 4000000-4500000,chr19: 4500000-5000000, chr19: 6500000-7000000, chr19: 7000000- 7500000,chr19: 7500000-8000000, chr19: 10000000-10500000, chr19:10500000-11000000, chr19: 11000000-11500000, chr19: 12500000-13000000,chr19: 13000000-13500000, chr19: 13500000-14000000, chr19:14000000-14500000, chr19: 14500000-15000000, chr19: 15000000-15500000,chr19: 15500000-16000000, chr19: 16500000-17000000, chr19:17000000-17500000, chr19: 18000000-18500000, chr19: 18500000-19000000,chr19: 19000000-19500000, chr19: 20500000-21000000, chr19:21000000-21500000, chr19: 21500000-22000000, chr19: 22000000-22500000,chr19: 22500000-23000000, chr19: 28000000-28500000, chr19:34000000-34500000, chr19: 35000000-35500000, chr19: 38000000-38500000,chr19: 38500000-39000000, chr19: 39000000-39500000, chr19:40500000-41000000, chr19: 41000000-41500000, chr19: 42000000-42500000,chr19: 42500000-43000000, chr19: 43500000-44000000, chr19:44500000-45000000, chr19: 45000000-45500000, chr19: 45500000-46000000,chr19: 46500000-47000000, chr19: 47000000-47500000, chr19:48500000-49000000, chr19: 49500000-50000000, chr19: 51000000-51500000,chr19: 54000000-54500000, chr19: 55000000-55500000, chr19:58500000-58617616 20 chr20: 1500000-2000000, chr20: 3500000-4000000,chr20: 4500000-5000000, chr20: 5000000- 5500000, chr20: 8000000-8500000,chr20: 10000000-10500000, chr20: 11500000-12000000, chr20:19000000-19500000, chr20: 20000000-20500000, chr20: 21500000-22000000,chr20: 24500000-25000000, chr20: 25500000-26000000, chr20:26000000-26500000, chr20: 28500000-29000000, chr20: 29000000-29500000,chr20: 29500000-30000000, chr20: 30000000-30500000, chr20:30500000-31000000, chr20: 31500000-32000000, chr20: 33000000-33500000,chr20: 34500000-35000000, chr20: 38500000-39000000, chr20:41000000-41500000, chr20: 45000000-45500000, chr20: 45500000-46000000,chr20: 48500000-49000000, chr20: 49000000-49500000, chr20:49500000-50000000, chr20: 50000000-50500000 21 chr21: 5000000-5500000,chr21: 5500000-6000000, chr21: 6000000-6500000, chr21: 6500000- 7000000,chr21: 7000000-7500000, chr21: 7500000-8000000, chr21: 8000000-8500000,chr21: 8500000-9000000, chr21: 9000000-9500000, chr21: 9500000-10000000,chr21: 10000000- 10500000, chr21: 10500000-11000000, chr21:13000000-13500000, chr21: 13500000-14000000, chr21: 25500000-26000000,chr21: 29000000-29500000, chr21: 34500000-35000000, chr21:42000000-42500000 22 chr22: 10500000-11000000, chr22: 11000000-11500000,chr22: 11500000-12000000, chr22: 12000000-12500000, chr22:12500000-13000000, chr22: 15000000-15500000, chr22: 15500000-16000000,chr22: 16000000-16500000, chr22: 16500000-17000000, chr22:18000000-18500000, chr22: 18500000-19000000, chr22: 21000000-21500000,chr22: 23000000-23500000, chr22: 31000000-31500000, chr22:31500000-32000000, chr22: 35500000-36000000, chr22: 36000000-36500000,chr22: 36500000-37000000, chr22: 39500000-40000000, chr22:41500000-42000000

TABLE 18 1 chr1: 500000-1000000, chr1: 1500000-2000000, chr1:3000000-3500000, chr1: 8000000-8500000, chr1: 8500000-9000000, chr1:9500000-10000000, chr1: 10000000-10500000, chr1: 11500000- 12000000,chr1: 12000000-12500000, chr1: 13000000-13500000, chr1:15500000-16000000, chr1: 16000000-16500000, chr1: 16500000-17000000,chr1: 19000000-19500000, chr1: 19500000- 20000000, chr1:20000000-20500000, chr1: 20500000-21000000, chr1: 21000000-21500000,chr1: 22000000-22500000, chr1: 23000000-23500000, chr1:24500000-25000000, chr1: 25500000- 26000000, chr1: 26500000-27000000,chr1: 27000000-27500000, chr1: 27500000-28000000, chr1:28000000-28500000, chr1: 28500000-29000000, chr1: 30500000-31000000,chr1: 31000000- 31500000, chr1: 31500000-32000000, chr1:32000000-32500000, chr1: 32500000-33000000, chr1: 33000000-33500000,chr1: 35000000-35500000, chr1: 35500000-36000000, chr1: 36000000-36500000, chr1: 36500000-37000000, chr1: 37500000-38000000, chr1:39000000-39500000, chr1: 39500000-40000000, chr1: 40000000-40500000,chr1: 40500000-41000000, chr1: 42000000- 42500000, chr1:42500000-43000000, chr1: 44500000-45000000, chr1: 45500000-46000000,chr1: 46000000-46500000, chr1: 49000000-49500000, chr1:51500000-52000000, chr1: 52000000- 52500000, chr1: 52500000-53000000,chr1: 53500000-54000000, chr1: 54000000-54500000, chr1:56500000-57000000, chr1: 58500000-59000000, chr1: 63500000-64000000,chr1: 65000000- 65500000, chr1: 66000000-66500000, chr1:67500000-68000000, chr1: 68500000-69000000, chr1: 70000000-70500000,chr1: 73000000-73500000, chr1: 77000000-77500000, chr1: 77500000-78000000, chr1: 79000000-79500000, chr1: 81500000-82000000, chr1:83000000-83500000, chr1: 88500000-89000000, chr1: 89500000-90000000,chr1: 90000000-90500000, chr1: 91500000- 92000000, chr1:93000000-93500000, chr1: 94500000-95000000, chr1: 98500000-99000000,chr1: 101000000-101500000, chr1: 104500000-105000000, chr1:107500000-108000000, chr1: 108500000-109000000, chr1:109000000-109500000, chr1: 109500000-110000000, chr1:110000000-110500000, chr1: 110500000-111000000, chr1:111500000-112000000, chr1: 112500000-113000000, chr1:114000000-114500000, chr1: 116000000-116500000, chr1:116500000-117000000, chr1: 118500000-119000000, chr1:120000000-120500000, chr1: 120500000-121000000, chr1:121000000-121500000, chr1: 125000000-125500000, chr1:143000000-143500000, chr1: 143500000-144000000, chr1:144000000-144500000, chr1: 144500000-145000000, chr1:145000000-145500000, chr1: 146000000-146500000, chr1:146500000-147000000, chr1: 147500000-148000000, chr1:148500000-149000000, chr1: 149000000-149500000, chr1:149500000-150000000, chr1: 150000000-150500000, chr1:150500000-151000000, chr1: 151000000-151500000, chr1:151500000-152000000, chr1: 152000000-152500000, chr1:153500000-154000000, chr1: 154500000-155000000, chr1:155000000-155500000, chr1: 155500000-156000000, chr1:156000000-156500000, chr1: 156500000-157000000, chr1:158000000-158500000, chr1: 158500000-159000000, chr1:159000000-159500000, chr1: 160000000-160500000, chr1:160500000-161000000, chr1: 161000000-161500000, chr1:162000000-162500000, chr1: 163500000-164000000, chr1:165500000-166000000, chr1: 167000000-167500000, chr1:169500000-170000000, chr1: 171500000-172000000, chr1:172500000-173000000, chr1: 173500000-174000000, chr1:175000000-175500000, chr1: 177500000-178000000, chr1:179000000-179500000, chr1: 181000000-181500000, chr1:182000000-182500000, chr1: 182500000-183000000, chr1:183000000-183500000, chr1: 183500000-184000000, chr1:184500000-185000000, chr1: 186000000-186500000, chr1:192500000-193000000, chr1: 198500000-199000000, chr1:200000000-200500000, chr1: 200500000-201000000, chr1:201500000-202000000, chr1: 202500000-203000000, chr1:203000000-203500000, chr1: 203500000-204000000, chr1:204000000-204500000, chr1: 205000000-205500000, chr1:206500000-207000000, chr1: 207000000-207500000, chr1:208000000-208500000, chr1: 211500000-212000000, chr1:212500000-213000000, chr1: 214000000-214500000, chr1:221500000-222000000, chr1: 222500000-223000000, chr1:224000000-224500000, chr1: 224500000-225000000, chr1:225500000-226000000, chr1: 226000000-226500000, chr1:229000000-229500000, chr1: 230500000-231000000, chr1:231500000-232000000, chr1: 232000000-232500000, chr1:233000000-233500000, chr1: 235000000-235500000, chr1:235500000-236000000, chr1: 242000000-242500000, chr1:242500000-243000000, chr1: 243500000-244000000, chr1:244000000-244500000, chr1: 244500000-245000000, chr1:246500000-247000000 2 chr2: 9500000-10000000, chr2: 13500000-14000000,chr2: 14500000-15000000, chr2: 15500000- 16000000, chr2:21500000-22000000, chr2: 24500000-25000000, chr2: 25500000-26000000,chr2: 26000000-26500000, chr2: 27000000-27500000, chr2:27500000-28000000, chr2: 28500000- 29000000, chr2: 30000000-30500000,chr2: 36500000-37000000, chr2: 37000000-37500000, chr2:37500000-38000000, chr2: 38500000-39000000, chr2: 39000000-39500000,chr2: 42000000- 42500000, chr2: 45500000-46000000, chr2:47500000-48000000, chr2: 48000000-48500000, chr2: 53000000-53500000,chr2: 54000000-54500000, chr2: 60500000-61000000, chr2: 61000000-61500000, chr2: 61500000-62000000, chr2: 62000000-62500000, chr2:64000000-64500000, chr2: 64500000-65000000, chr2: 65000000-65500000,chr2: 68000000-68500000, chr2: 69000000- 69500000, chr2:69500000-70000000, chr2: 70000000-70500000, chr2: 70500000-71000000,chr2: 71000000-71500000, chr2: 71500000-72000000, chr2:72000000-72500000, chr2: 74500000- 75000000, chr2: 76000000-76500000,chr2: 76500000-77000000, chr2: 78500000-79000000, chr2:79000000-79500000, chr2: 81000000-81500000, chr2: 84000000-84500000,chr2: 84500000- 85000000, chr2: 85500000-86000000, chr2:87000000-87500000, chr2: 87500000-88000000, chr2: 89000000-89500000,chr2: 89500000-90000000, chr2: 90000000-90500000, chr2: 91000000-91500000, chr2: 91500000-92000000, chr2: 92000000-92500000, chr2:94500000-95000000, chr2: 96000000-96500000, chr2: 96500000-97000000,chr2: 97000000-97500000, chr2: 97500000- 98000000, chr2:99000000-99500000, chr2: 101500000-102000000, chr2: 102000000-102500000,chr2: 103000000-103500000, chr2: 105500000-106000000, chr2:107500000-108000000, chr2: 109500000-110000000, chr2:112500000-113000000, chr2: 113500000-114000000, chr2:114500000-115000000, chr2: 116000000-116500000, chr2:117000000-117500000, chr2: 119500000-120000000, chr2:122000000-122500000, chr2: 125000000-125500000, chr2:126500000-127000000, chr2: 128000000-128500000, chr2:129000000-129500000, chr2: 129500000-130000000, chr2:130000000-130500000, chr2: 130500000-131000000, chr2:131500000-132000000, chr2: 132000000-132500000, chr2:133000000-133500000, chr2: 134000000-134500000, chr2:135500000-136000000, chr2: 136000000-136500000, chr2:143000000-143500000, chr2: 143500000-144000000, chr2:144000000-144500000, chr2: 144500000-145000000, chr2:145500000-146000000, chr2: 147500000-148000000, chr2:148500000-149000000, chr2: 150000000-150500000, chr2:150500000-151000000, chr2: 151000000-151500000, chr2:153000000-153500000, chr2: 156000000-156500000, chr2:158000000-158500000, chr2: 161000000-161500000, chr2:162000000-162500000, chr2: 165500000-166000000, chr2:168000000-168500000, chr2: 168500000-169000000, chr2:171000000-171500000, chr2: 171500000-172000000, chr2:174500000-175000000, chr2: 176000000-176500000, chr2:177000000-177500000, chr2: 178000000-178500000, chr2:181000000-181500000, chr2: 181500000-182000000, chr2:183500000-184000000, chr2: 189500000-190000000, chr2:190000000-190500000, chr2: 190500000-191000000, chr2:196000000-196500000, chr2: 197000000-197500000, chr2:198000000-198500000, chr2: 200500000-201000000, chr2:201000000-201500000, chr2: 204000000-204500000, chr2:207000000-207500000, chr2: 207500000-208000000, chr2:208500000-209000000, chr2: 215500000-216000000, chr2:216000000-216500000, chr2: 217500000-218000000, chr2:218000000-218500000, chr2: 218500000-219000000, chr2:219000000-219500000, chr2: 220000000-220500000, chr2:224500000-225000000, chr2: 225000000-225500000, chr2:226000000-226500000, chr2: 226500000-227000000, chr2:227000000-227500000, chr2: 228000000-228500000, chr2:230000000-230500000, chr2: 230500000-231000000, chr2:231000000-231500000, chr2: 231500000-232000000, chr2:235500000-236000000, chr2: 238500000-239000000, chr2:240500000-241000000 3 chr3: 500000-1000000, chr3: 6500000-7000000, chr3:9000000-9500000, chr3: 9500000-10000000, chr3: 10000000-10500000, chr3:12500000-13000000, chr3: 13500000-14000000, chr3: 14000000- 14500000,chr3: 16500000-17000000, chr3: 17000000-17500000, chr3:22000000-22500000, chr3: 23500000-24000000, chr3: 25500000-26000000,chr3: 30000000-30500000, chr3: 30500000- 31000000, chr3:31500000-32000000, chr3: 32500000-33000000, chr3: 33000000-33500000,chr3: 36500000-37000000, chr3: 37000000-37500000, chr3:39000000-39500000, chr3: 42000000- 42500000, chr3: 43500000-44000000,chr3: 45000000-45500000, chr3: 46000000-46500000, chr3:47000000-47500000, chr3: 47500000-48000000, chr3: 48500000-49000000,chr3: 49000000- 49500000, chr3: 49500000-50000000, chr3:51500000-52000000, chr3: 52000000-52500000, chr3: 56500000-57000000,chr3: 57500000-58000000, chr3: 58500000-59000000, chr3: 59000000-59500000, chr3: 64500000-65000000, chr3: 65000000-65500000, chr3:66000000-66500000, chr3: 67500000-68000000, chr3: 68500000-69000000,chr3: 69000000-69500000, chr3: 69500000- 70000000, chr3:70000000-70500000, chr3: 71000000-71500000, chr3: 71500000-72000000,chr3: 72000000-72500000, chr3: 72500000-73000000, chr3:73500000-74000000, chr3: 75000000- 75500000, chr3: 75500000-76000000,chr3: 76500000-77000000, chr3: 77500000-78000000, chr3:78000000-78500000, chr3: 88500000-89000000, chr3: 89000000-89500000,chr3: 89500000- 90000000, chr3: 91000000-91500000, chr3:95500000-96000000, chr3: 101500000-102000000, chr3: 107500000-108000000,chr3: 108000000-108500000, chr3: 112000000-112500000, chr3:113000000-113500000, chr3: 116500000-117000000, chr3:119500000-120000000, chr3: 122000000-122500000, chr3:127000000-127500000, chr3: 128500000-129000000, chr3:129000000-129500000, chr3: 135000000-135500000, chr3:135500000-136000000, chr3: 141000000-141500000, chr3:141500000-142000000, chr3: 143000000-143500000, chr3:143500000-144000000, chr3: 147500000-148000000, chr3:148000000-148500000, chr3: 150000000-150500000, chr3:151000000-151500000, chr3: 152000000-152500000, chr3:155500000-156000000, chr3: 156500000-157000000, chr3:157000000-157500000, chr3: 161000000-161500000, chr3:161500000-162000000, chr3: 162000000-162500000, chr3:163000000-163500000, chr3: 166500000-167000000, chr3:169500000-170000000, chr3: 170000000-170500000, chr3:171000000-171500000, chr3: 171500000-172000000, chr3:172000000-172500000, chr3: 179500000-180000000, chr3:183000000-183500000, chr3: 184000000-184500000, chr3:184500000-185000000, chr3: 186000000-186500000, chr3:186500000-187000000, chr3: 187500000-188000000, chr3:188500000-189000000, chr3: 189000000-189500000, chr3:191500000-192000000, chr3: 192000000-192500000, chr3:194500000-195000000, chr3: 197000000-197500000, chr3:198000000-198295559 4 chr4: 2500000-3000000, chr4: 6000000-6500000,chr4: 8500000-9000000, chr4: 9000000-9500000, chr4: 9500000-10000000,chr4: 10000000-10500000, chr4: 15000000-15500000, chr4: 25000000-25500000, chr4: 26000000-26500000, chr4: 27000000-27500000, chr4:27500000-28000000, chr4: 36000000-36500000, chr4: 37500000-38000000,chr4: 38000000-38500000, chr4: 38500000- 39000000, chr4:39500000-40000000, chr4: 40000000-40500000, chr4: 40500000-41000000,chr4: 45000000-45500000, chr4: 47500000-48000000, chr4:49000000-49500000, chr4: 49500000- 50000000, chr4: 52000000-52500000,chr4: 57500000-58000000, chr4: 58000000-58500000, chr4:59000000-59500000, chr4: 60500000-61000000, chr4: 61500000-62000000,chr4: 62000000- 62500000, chr4: 65000000-65500000, chr4:66500000-67000000, chr4: 67500000-68000000, chr4: 68000000-68500000,chr4: 68500000-69000000, chr4: 70500000-71000000, chr4: 74000000-74500000, chr4: 77000000-77500000, chr4: 78500000-79000000, chr4:80000000-80500000, chr4: 80500000-81000000, chr4: 83000000-83500000,chr4: 83500000-84000000, chr4: 84500000- 85000000, chr4:88500000-89000000, chr4: 89000000-89500000, chr4: 98500000-99000000,chr4: 99500000-100000000, chr4: 101000000-101500000, chr4:102000000-102500000, chr4: 103000000-103500000, chr4:105000000-105500000, chr4: 108000000-108500000, chr4:111000000-111500000, chr4: 111500000-112000000, chr4:113500000-114000000, chr4: 117500000-118000000, chr4:121500000-122000000, chr4: 126500000-127000000, chr4:129500000-130000000, chr4: 130500000-131000000, chr4:131500000-132000000, chr4: 133500000-134000000, chr4:135000000-135500000, chr4: 140000000-140500000, chr4:142000000-142500000, chr4: 151000000-151500000, chr4:152500000-153000000, chr4: 153000000-153500000, chr4:153500000-154000000, chr4: 156000000-156500000, chr4:160000000-160500000, chr4: 164500000-165000000, chr4:165500000-166000000, chr4: 167000000-167500000, chr4:171500000-172000000, chr4: 172000000-172500000, chr4:175000000-175500000, chr4: 178500000-179000000, chr4:184000000-184500000, chr4: 184500000-185000000, chr4:185500000-186000000, chr4: 187000000-187500000, chr4:187500000-188000000, chr4: 188000000-188500000, chr4:188500000-189000000, chr4: 189500000-190000000, chr4:190000000-190214555 5 chr5: 1500000-2000000, chr5: 2000000-2500000,chr5: 3000000-3500000, chr5: 4000000-4500000, chr5: 4500000-5000000,chr5: 7000000-7500000, chr5: 9000000-9500000, chr5: 9500000- 10000000,chr5: 10500000-11000000, chr5: 13500000-14000000, chr5:14500000-15000000, chr5: 16000000-16500000, chr5: 17500000-18000000,chr5: 19000000-19500000, chr5: 20000000- 20500000, chr5:21000000-21500000, chr5: 22500000-23000000, chr5: 23000000-23500000,chr5: 26000000-26500000, chr5: 31500000-32000000, chr5:34000000-34500000, chr5: 36500000- 37000000, chr5: 39000000-39500000,chr5: 40500000-41000000, chr5: 43000000-43500000, chr5:44000000-44500000, chr5: 45500000-46000000, chr5: 50500000-51000000,chr5: 51000000- 51500000, chr5: 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132500000, chr5:132500000-133000000, chr5: 134500000-135000000, chr5: 136500000-137000000, chr5: 137500000-138000000, chr5: 138000000-138500000, chr5:138500000- 139000000, chr5: 139000000-139500000, chr5:139500000-140000000, chr5: 140500000 141000000, chr5:141000000-141500000, chr5: 141500000-142000000, chr5: 142000000-142500000, chr5: 142500000-143000000, chr5: 143000000-143500000, chr5:146000000- 146500000, chr5: 148500000-149000000, chr5:149000000-149500000, chr5: 149500000- 150000000, chr5:151000000-151500000, chr5: 151500000-152000000, chr5: 157000000-157500000, chr5: 157500000-158000000, chr5: 158000000-158500000, chr5:159000000 159500000, chr5: 160000000-160500000, chr5:161500000-162000000, chr5: 162500000- 163000000, chr5:166500000-167000000, chr5: 169500000-170000000, chr5: 170000000-170500000, chr5: 171500000-172000000, chr5: 172500000-173000000, chr5:177000000- 177500000, chr5: 180000000-180500000, chr5:181000000-181500000 6 chr6: 2500000-3000000, chr6: 4000000-4500000,chr6: 6500000-7000000, chr6: 8500000-9000000, chr6: 9000000-9500000,chr6: 10500000-11000000, chr6: 11000000-11500000, chr6: 12000000-12500000, chr6: 13500000-14000000, chr6: 14000000-14500000, chr6:14500000-15000000, chr6: 15000000-15500000, chr6: 16000000-16500000,chr6: 17500000-18000000, chr6: 18000000- 18500000, chr6:19500000-20000000, chr6: 20000000-20500000, chr6: 25000000-25500000,chr6: 25500000-26000000, chr6: 26000000-26500000, chr6:27500000-28000000, chr6: 29500000- 30000000, chr6: 30000000-30500000,chr6: 30500000-31000000, chr6: 31000000-31500000, chr6:31500000-32000000, chr6: 32500000-33000000, chr6: 33000000-33500000,chr6: 33500000- 34000000, chr6: 34500000-35000000, chr6:35000000-35500000, chr6: 36000000-36500000, chr6: 36500000-37000000,chr6: 37000000-37500000, chr6: 37500000-38000000, chr6: 40500000-41000000, chr6: 41000000-41500000, chr6: 41500000-42000000, chr6:42500000-43000000, chr6: 43000000-43500000, chr6: 44000000-44500000,chr6: 47000000-47500000, chr6: 49500000- 50000000, chr6:51000000-51500000, chr6: 53000000-53500000, chr6: 53500000-54000000,chr6: 55500000-56000000, chr6: 57500000-58000000, chr6:58000000-58500000, chr6: 58500000- 59000000, chr6: 60000000-60500000,chr6: 60500000-61000000, chr6: 62000000-62500000, chr6:63500000-64000000, chr6: 68500000-69000000, chr6: 70500000-71000000,chr6: 74000000- 74500000, chr6: 74500000-75000000, chr6:77000000-77500000, chr6: 87500000-88000000, chr6: 88500000-89000000,chr6: 89000000-89500000, chr6: 92500000-93000000, chr6: 94500000-95000000, chr6: 97000000-97500000, chr6: 104000000-104500000, chr6:105500000-106000000, chr6: 106000000-106500000, chr6:108500000-109000000, chr6: 110500000-111000000, chr6:111000000-111500000, chr6: 111500000-112000000, chr6:112000000-112500000, chr6: 112500000-113000000, chr6:119000000-119500000, chr6: 119500000-120000000, chr6:128000000-128500000, chr6: 129500000-130000000, chr6:130000000-130500000, chr6: 130500000-131000000, chr6:133000000-133500000, chr6: 134000000-134500000, chr6:134500000-135000000, chr6: 135000000-135500000, chr6:135500000-136000000, chr6: 137000000-137500000, chr6:137500000-138000000, chr6: 138000000-138500000, chr6:139000000-139500000, chr6: 143500000-144000000, chr6:144000000-144500000, chr6: 147000000-147500000, chr6:149000000-149500000, chr6: 149500000-150000000, chr6:154000000-154500000, chr6: 159500000-160000000, chr6:162000000-162500000, chr6: 165000000-165500000, chr6:168000000-168500000 7 chr7: 6000000-6500000, chr7: 7500000-8000000,chr7: 26000000-26500000, chr7: 27000000- 27500000, chr7:30000000-30500000, chr7: 32000000-32500000, chr7: 37000000-37500000,chr7: 39500000-40000000, chr7: 45500000-46000000, chr7:46000000-46500000, chr7: 48000000- 48500000, chr7: 51500000-52000000,chr7: 53000000-53500000, chr7: 53500000-54000000, chr7:54000000-54500000, chr7: 56000000-56500000, chr7: 56500000-57000000,chr7: 57000000- 57500000, chr7: 57500000-58000000, chr7:58000000-58500000, chr7: 63000000-63500000, chr7: 63500000-64000000,chr7: 65000000-65500000, chr7: 66500000-67000000, chr7: 68000000-68500000, chr7: 72000000-72500000, chr7: 73500000-74000000, chr7:74500000-75000000, chr7: 75500000-76000000, chr7: 77500000-78000000,chr7: 88000000-88500000, chr7: 89500000- 90000000, chr7:97500000-98000000, chr7: 98000000-98500000, chr7: 99000000-99500000,chr7: 100000000-100500000, chr7: 100500000-101000000, chr7:101000000-101500000, chr7: 103000000-103500000, chr7:105500000-106000000, chr7: 106000000-106500000, chr7:107000000-107500000, chr7: 109500000-110000000, chr7:112000000-112500000, chr7: 112500000-113000000, chr7:114500000-115000000, chr7: 116000000-116500000, chr7:127500000-128000000, chr7: 128000000-128500000, chr7:129000000-129500000, chr7: 129500000-130000000, chr7:130000000-130500000, chr7: 130500000-131000000, chr7:131000000-131500000, chr7: 131500000-132000000, chr7:137000000-137500000, chr7: 139000000-139500000, chr7:140000000-140500000, chr7: 147500000-148000000, chr7:148500000-149000000, chr7: 149000000-149500000, chr7:151000000-151500000, chr7: 151500000-152000000, chr7:152500000-153000000, chr7: 153500000-154000000, chr7:154000000-154500000 8 chr8: 0-500000, chr8: 3000000-3500000, chr8:4000000-4500000, chr8: 7000000-7500000, chr8: 7500000-8000000, chr8:8000000-8500000, chr8: 11000000-11500000, chr8: 12000000- 12500000,chr8: 12500000-13000000, chr8: 18000000-18500000, chr8:19500000-20000000, chr8: 20000000-20500000, chr8: 20500000-21000000,chr8: 21000000-21500000, chr8: 22500000- 23000000, chr8:23500000-24000000, chr8: 25000000-25500000, chr8: 27000000-27500000,chr8: 28500000-29000000, chr8: 30000000-30500000, chr8:30500000-31000000, chr8: 32500000- 33000000, chr8: 35000000-35500000,chr8: 35500000-36000000, chr8: 36000000-36500000, chr8:37500000-38000000, chr8: 42000000-42500000, chr8: 42500000-43000000,chr8: 43500000- 44000000, chr8: 47500000-48000000, chr8:49000000-49500000, chr8: 55000000-55500000, chr8: 58500000-59000000,chr8: 60500000-61000000, chr8: 62000000-62500000, chr8: 64500000-65000000, chr8: 66000000-66500000, chr8: 66500000-67000000, chr8:68500000-69000000, chr8: 69000000-69500000, chr8: 70000000-70500000,chr8: 72000000-72500000, chr8: 73500000- 74000000, chr8:74500000-75000000, chr8: 77000000-77500000, chr8: 79500000-80000000,chr8: 85500000-86000000, chr8: 87000000-87500000, chr8:87500000-88000000, chr8: 88000000- 88500000, chr8: 91500000-92000000,chr8: 94500000-95000000, chr8: 95000000-95500000, chr8:96500000-97000000, chr8: 101000000-101500000, chr8: 104000000-104500000,chr8: 106000000-106500000, chr8: 115000000-115500000, chr8:120500000-121000000, chr8: 121500000-122000000, chr8:122500000-123000000, chr8: 123500000-124000000, chr8:124000000-124500000, chr8: 124500000-125000000, chr8:125000000-125500000, chr8: 127500000-128000000, chr8:128000000-128500000, chr8: 128500000-129000000, chr8:130000000-130500000, chr8: 130500000-131000000, chr8:133000000-133500000, chr8: 134000000-134500000, chr8:138000000-138500000, chr8: 139500000-140000000, chr8:140000000-140500000, chr8: 140500000-141000000 9 chr9: 3500000-4000000,chr9: 4500000-5000000, chr9: 5500000-6000000, chr9: 10500000- 11000000,chr9: 15000000-15500000, chr9: 17000000-17500000, chr9:19000000-19500000, chr9: 21000000-21500000, chr9: 23500000-24000000,chr9: 33000000-33500000, chr9: 34000000- 34500000, chr9:34500000-35000000, chr9: 35000000-35500000, chr9: 35500000-36000000,chr9: 36000000-36500000, chr9: 37000000-37500000, chr9:37500000-38000000, chr9: 39000000- 39500000, chr9: 39500000-40000000,chr9: 40000000-40500000, chr9: 40500000-41000000, chr9:41000000-41500000, chr9: 41500000-42000000, chr9: 42000000-42500000,chr9: 42500000- 43000000, chr9: 43000000-43500000, chr9:60500000-61000000, chr9: 61500000-62000000, chr9: 62000000-62500000,chr9: 62500000-63000000, chr9: 63000000-63500000, chr9: 63500000-64000000, chr9: 64000000-64500000, chr9: 64500000-65000000, chr9:65000000-65500000, chr9: 65500000-66000000, chr9: 66000000-66500000,chr9: 66500000-67000000, chr9: 67000000- 67500000, chr9:67500000-68000000, chr9: 75000000-75500000, chr9: 78000000-78500000,chr9: 80500000-81000000, chr9: 83500000-84000000, chr9:84000000-84500000, chr9: 85500000- 86000000, chr9: 86500000-87000000,chr9: 87000000-87500000, chr9: 89000000-89500000, chr9:99000000-99500000, chr9: 102000000-102500000, chr9: 103000000-103500000,chr9: 105000000-105500000, chr9: 106000000-106500000, chr9:109000000-109500000, chr9: 113500000-114000000, chr9:114500000-115000000, chr9: 117000000-117500000, chr9:117500000-118000000, chr9: 120500000-121000000, chr9:122000000-122500000, chr9: 124500000-125000000, chr9:125000000-125500000, chr9: 125500000-126000000, chr9:126500000-127000000, chr9: 128000000-128500000, chr9:128500000-129000000, chr9: 129000000-129500000, chr9:129500000-130000000, chr9: 132000000-132500000, chr9:135000000-135500000 10 chr10: 0-500000, chr10: 2000000-2500000, chr10:3000000-3500000, chr10: 3500000-4000000, chr10: 4000000-4500000, chr10:6000000-6500000, chr10: 7000000-7500000, chr10: 8000000- 8500000, chr10:9000000-9500000, chr10: 13500000-14000000, chr10: 16500000-17000000,chr10: 19000000-19500000, chr10: 20500000-21000000, chr10:23000000-23500000, chr10: 27500000-28000000, chr10: 28000000-28500000,chr10: 30000000-30500000, chr10: 31500000-32000000, chr10:35000000-35500000, chr10: 35500000-36000000, chr10: 36500000-37000000,chr10: 37000000-37500000, chr10: 38000000-38500000, chr10:38500000-39000000, chr10: 42000000-42500000, chr10: 42500000-43000000,chr10: 43000000-43500000, chr10: 44000000-44500000, chr10:46500000-47000000, chr10: 47500000-48000000, chr10: 52000000-52500000,chr10: 52500000-53000000, chr10: 55500000-56000000, chr10:58000000-58500000, chr10: 62000000-62500000, chr10: 63000000-63500000,chr10: 64000000-64500000, chr10: 68000000-68500000, chr10:69000000-69500000, chr10: 72000000-72500000, chr10: 73000000-73500000,chr10: 73500000-74000000, chr10: 74500000-75000000, chr10:76500000-77000000, chr10: 79000000-79500000, chr10: 84500000-85000000,chr10: 87000000-87500000, chr10: 88000000-88500000, chr10:89000000-89500000, chr10: 92500000-93000000, chr10: 94500000-95000000,chr10: 96500000-97000000, chr10: 97000000-97500000, chr10:97500000-98000000, chr10: 99000000-99500000, chr10: 100000000-100500000,chr10: 100500000-101000000, chr10: 101000000-101500000, chr10:102000000-102500000, chr10: 102500000-103000000, chr10:104000000-104500000, chr10: 108000000-108500000, chr10:109000000-109500000, chr10: 109500000-110000000, chr10:110000000-110500000, chr10: 111500000-112000000, chr10:117000000-117500000, chr10: 119000000-119500000, chr10:119500000-120000000, chr10: 120500000-121000000, chr10:125500000-126000000, chr10: 126500000-127000000, chr10:127000000-127500000, chr10: 127500000-128000000, chr10:128500000-129000000, chr10: 129500000-130000000, chr10:130000000-130500000, chr10: 130500000-131000000, chr10:133500000-133797422 11 chr11: 2500000-3000000, chr11: 4500000-5000000,chr11: 5500000-6000000, chr11: 6000000- 6500000, chr11: 6500000-7000000,chr11: 9000000-9500000, chr11: 10500000-11000000, chr11:13000000-13500000, chr11: 18000000-18500000, chr11: 20500000-21000000,chr11: 23000000-23500000, chr11: 24000000-24500000, chr11:25500000-26000000, chr11: 27500000-28000000, chr11: 29000000-29500000,chr11: 33000000-33500000, chr11: 33500000-34000000, chr11:35000000-35500000, chr11: 37500000-38000000, chr11: 38000000-38500000,chr11: 39500000-40000000, chr11: 40000000-40500000, chr11:40500000-41000000, chr11: 41500000-42000000, chr11: 43500000-44000000,chr11: 44500000-45000000, chr11: 46000000-46500000, chr11:47000000-47500000, chr11: 47500000-48000000, chr11: 48500000-49000000,chr11: 49000000-49500000, chr11: 49500000-50000000, chr11:50000000-50500000, chr11: 55500000-56000000, chr11: 56500000-57000000,chr11: 57500000-58000000, chr11: 59500000-60000000, chr11:61000000-61500000, chr11: 61500000-62000000, chr11: 62500000-63000000,chr11: 63500000-64000000, chr11: 64000000-64500000, chr11:64500000-65000000, chr11: 65000000-65500000, chr11: 65500000-66000000,chr11: 66000000-66500000, chr11: 67000000-67500000, chr11:68500000-69000000, chr11: 72000000-72500000, chr11: 72500000-73000000,chr11: 77000000-77500000, chr11: 77500000-78000000, chr11:78000000-78500000, chr11: 80000000-80500000, chr11: 85500000-86000000,chr11: 86000000-86500000, chr11: 89000000-89500000, chr11:89500000-90000000, chr11: 92000000-92500000, chr11: 93000000-93500000,chr11: 93500000-94000000, chr11: 95000000-95500000, chr11:95500000-96000000, chr11: 96500000-97000000, chr11: 99500000-100000000,chr11: 100000000-100500000, chr11: 101000000-101500000, chr11:101500000-102000000, chr11: 102000000-102500000, chr11:104000000-104500000, chr11: 104500000-105000000, chr11:106500000-107000000, chr11: 107000000-107500000, chr11:108500000-109000000, chr11: 109000000-109500000, chr11:111500000-112000000, chr11: 114000000-114500000, chr11:116500000-117000000, chr11: 117500000-118000000, chr11:118000000-118500000, chr11: 118500000-119000000, chr11:119000000-119500000, chr11: 121000000-121500000, chr11:122500000-123000000, chr11: 125500000-126000000, chr11:127000000-127500000, chr11: 128500000-129000000, chr11:130000000-130500000, chr11: 133500000-134000000, chr11:135000000-135086622 12 chr12: 500000-1000000, chr12: 1500000-2000000,chr12: 6000000-6500000, chr12: 6500000- 7000000, chr12: 7500000-8000000,chr12: 8500000-9000000, chr12: 9500000-10000000, chr12:10500000-11000000, chr12: 11000000-11500000, chr12: 11500000-12000000,chr12: 12000000-12500000, chr12: 12500000-13000000, chr12:13000000-13500000, chr12: 17000000-17500000, chr12: 18000000-18500000,chr12: 25500000-26000000, chr12: 26000000-26500000, chr12:27000000-27500000, chr12: 33000000-33500000, chr12: 34500000-35000000,chr12: 37000000-37500000, chr12: 38500000-39000000, chr12:40500000-41000000, chr12: 41000000-41500000, chr12: 42000000-42500000,chr12: 42500000-43000000, chr12: 47500000-48000000, chr12:48500000-49000000, chr12: 49000000-49500000, chr12: 49500000-50000000,chr12: 50000000-50500000, chr12: 50500000-51000000, chr12:51000000-51500000, chr12: 53000000-53500000, chr12: 53500000-54000000,chr12: 54000000-54500000, chr12: 56000000-56500000, chr12:57000000-57500000, chr12: 57500000-58000000, chr12: 58000000-58500000,chr12: 58500000-59000000, chr12: 60500000-61000000, chr12:61000000-61500000, chr12: 62000000-62500000, chr12: 64500000-65000000,chr12: 66000000-66500000, chr12: 67500000-68000000, chr12:68000000-68500000, chr12: 70500000-71000000, chr12: 71500000-72000000,chr12: 73000000-73500000, chr12: 75500000-76000000, chr12:76000000-76500000, chr12: 76500000-77000000, chr12: 83500000-84000000,chr12: 84000000-84500000, chr12: 88000000-88500000, chr12:89000000-89500000, chr12: 91500000-92000000, chr12: 93000000-93500000,chr12: 93500000-94000000, chr12: 94500000-95000000, chr12:96000000-96500000, chr12: 98500000-99000000, chr12: 101500000-102000000,chr12: 102500000-103000000, chr12: 104000000-104500000, chr12:104500000-105000000, chr12: 105000000-105500000, chr12:106500000-107000000, chr12: 108500000-109000000, chr12:109500000-110000000, chr12: 110000000-110500000, chr12:110500000-111000000, chr12: 111000000-111500000, chr12:112000000-112500000, chr12: 112500000-113000000, chr12:113000000-113500000, chr12: 116000000-116500000, chr12:116500000-117000000, chr12: 118000000-118500000, chr12:120000000-120500000, chr12: 120500000-121000000, chr12:121000000-121500000, chr12: 121500000-122000000, chr12:122000000-122500000, chr12: 122500000-123000000, chr12:127500000-128000000 13 chr13: 16000000-16500000, chr13:18000000-18500000, chr13: 18500000-19000000, chr13: 19000000-19500000,chr13: 20500000-21000000, chr13: 27000000-27500000, chr13:28000000-28500000, chr13: 30000000-30500000, chr13: 30500000-31000000,chr13: 34500000-35000000, chr13: 35500000-36000000, chr13:37500000-38000000, chr13: 38500000-39000000, chr13: 40000000-40500000,chr13: 41000000-41500000, chr13: 44000000-44500000, chr13:45000000-45500000, chr13: 46000000-46500000, chr13: 48500000-49000000,chr13: 49500000-50000000, chr13: 50000000-50500000, chr13:54000000-54500000, chr13: 56500000-57000000, chr13: 57000000-57500000,chr13: 60500000-61000000, chr13: 66500000-67000000, chr13:67000000-67500000, chr13: 67500000-68000000, chr13: 68000000-68500000,chr13: 73000000-73500000, chr13: 75500000-76000000, chr13:85000000-85500000, chr13: 90500000-91000000, chr13: 92500000-93000000,chr13: 93500000-94000000, chr13: 94000000-94500000, chr13:97500000-98000000, chr13: 99000000-99500000, chr13: 100000000-100500000,chr13: 102000000-102500000, chr13: 102500000-103000000, chr13:104000000-104500000, chr13: 107000000-107500000, chr13:112000000-112500000 14 chr14: 18000000-18500000, chr14:18500000-19000000, chr14: 19000000-19500000, chr14: 19500000-20000000,chr14: 21000000-21500000, chr14: 22500000-23000000, chr14:23000000-23500000, chr14: 25500000-26000000, chr14: 27000000-27500000,chr14: 28000000-28500000, chr14: 29000000-29500000, chr14:29500000-30000000, chr14: 30500000-31000000, chr14: 34500000-35000000,chr14: 35000000-35500000, chr14: 35500000-36000000, chr14:36500000-37000000, chr14: 39000000-39500000, chr14: 39500000-40000000,chr14: 43000000-43500000, chr14: 45500000-46000000, chr14:47000000-47500000, chr14: 47500000-48000000, chr14: 48000000-48500000,chr14: 49500000-50000000, chr14: 50500000-51000000, chr14:51500000-52000000, chr14: 55000000-55500000, chr14: 55500000-56000000,chr14: 58000000-58500000, chr14: 59000000-59500000, chr14:61000000-61500000, chr14: 63500000-64000000, chr14: 64500000-65000000,chr14: 65000000-65500000, chr14: 67500000-68000000, chr14:68500000-69000000, chr14: 69000000-69500000, chr14: 69500000-70000000,chr14: 70500000-71000000, chr14: 73000000-73500000, chr14:74000000-74500000, chr14: 75000000-75500000, chr14: 77000000-77500000,chr14: 79500000-80000000, chr14: 80500000-81000000, chr14:82000000-82500000, chr14: 83000000-83500000, chr14: 86000000-86500000,chr14: 86500000-87000000, chr14: 87000000-87500000, chr14:88500000-89000000, chr14: 89000000-89500000, chr14: 91000000-91500000,chr14: 92000000-92500000, chr14: 94000000-94500000, chr14:97000000-97500000, chr14: 97500000-98000000, chr14: 98000000-98500000,chr14: 100000000-100500000, chr14: 101000000-101500000 15 chr15:17000000-17500000, chr15: 19500000-20000000, chr15: 20000000-20500000,chr15: 20500000-21000000, chr15: 21000000-21500000, chr15:21500000-22000000, chr15: 22000000-22500000, chr15: 23000000-23500000,chr15: 24000000-24500000, chr15: 24500000-25000000, chr15:25000000-25500000, chr15: 26500000-27000000, chr15: 27500000-28000000,chr15: 28000000-28500000, chr15: 28500000-29000000, chr15:30000000-30500000, chr15: 32000000-32500000, chr15: 34000000-34500000,chr15: 36000000-36500000, chr15: 39500000-40000000, chr15:40500000-41000000, chr15: 41000000-41500000, chr15: 41500000-42000000,chr15: 42000000-42500000, chr15: 42500000-43000000, chr15:43000000-43500000, chr15: 43500000-44000000, chr15: 46000000-46500000,chr15: 48500000-49000000, chr15: 50000000-50500000, chr15:53000000-53500000, chr15: 55000000-55500000, chr15: 57000000-57500000,chr15: 58000000-58500000, chr15: 60000000-60500000, chr15:62000000-62500000, chr15: 63000000-63500000, chr15: 63500000-64000000,chr15: 64000000-64500000, chr15: 64500000-65000000, chr15:65500000-66000000, chr15: 68500000-69000000, chr15: 69000000-69500000,chr15: 69500000-70000000, chr15: 70000000-70500000, chr15:72500000-73000000, chr15: 73000000-73500000, chr15: 78000000-78500000,chr15: 79000000-79500000, chr15: 81000000-81500000, chr15:82000000-82500000, chr15: 84000000-84500000, chr15: 85500000-86000000,chr15: 89000000-89500000, chr15: 90000000-90500000, chr15:90500000-91000000, chr15: 91500000-92000000, chr15: 92500000-93000000,chr15: 94000000-94500000, chr15: 96500000-97000000, chr15:97500000-98000000 6 chr16: 4000000-4500000, chr16: 4500000-5000000,chr16: 9000000-9500000, chr16: 10500000- 11000000, chr16:11500000-12000000, chr16: 12000000-12500000, chr16: 12500000-13000000,chr16: 15500000-16000000, chr16: 17000000-17500000, chr16:18000000-18500000, chr16: 22000000-22500000, chr16: 23500000-24000000,chr16: 24000000-24500000, chr16: 24500000-25000000, chr16:26500000-27000000, chr16: 27000000-27500000, chr16: 28500000-29000000,chr16: 29000000-29500000, chr16: 29500000-30000000, chr16:30000000-30500000, chr16: 30500000-31000000, chr16: 31000000-31500000,chr16: 32000000-32500000, chr16: 32500000-33000000, chr16:33000000-33500000, chr16: 33500000-34000000, chr16: 34000000-34500000,chr16: 34500000-35000000, chr16: 35000000-35500000, chr16:46000000-46500000, chr16: 46500000-47000000, chr16: 48000000-48500000,chr16: 53000000-53500000, chr16: 53500000-54000000, chr16:57000000-57500000, chr16: 58000000-58500000, chr16: 61000000-61500000,chr16: 63000000-63500000, chr16: 67500000-68000000, chr16:68000000-68500000, chr16: 69000000-69500000, chr16: 71500000-72000000,chr16: 74500000-75000000, chr16: 79000000-79500000, chr16:81000000-81500000, chr16: 81500000-82000000, chr16: 84500000-85000000,chr16: 85000000-85500000, chr16: 90000000-90338345 17 chr17: 0-500000,chr17: 1000000-1500000, chr17: 1500000-2000000, chr17: 2000000-2500000,chr17: 2500000-3000000, chr17: 4500000-5000000, chr17: 7000000-7500000,chr17: 7500000- 8000000, chr17: 8000000-8500000, chr17: 8500000-9000000,chr17: 10000000-10500000, chr17: 11000000-11500000, chr17:13500000-14000000, chr17: 14000000-14500000, chr17: 17500000-18000000,chr17: 19000000-19500000, chr17: 20500000-21000000, chr17:21000000-21500000, chr17: 21500000-22000000, chr17: 22000000-22500000,chr17: 22500000-23000000, chr17: 26500000-27000000, chr17:28000000-28500000, chr17: 28500000-29000000, chr17: 29500000-30000000,chr17: 30000000-30500000, chr17: 32000000-32500000, chr17:35000000-35500000, chr17: 35500000-36000000, chr17: 36000000-36500000,chr17: 36500000-37000000, chr17: 38000000-38500000, chr17:38500000-39000000, chr17: 39000000-39500000, chr17: 39500000-40000000,chr17: 40000000-40500000, chr17: 41500000-42000000, chr17:42000000-42500000, chr17: 42500000-43000000, chr17: 43500000-44000000,chr17: 44000000-44500000, chr17: 45000000-45500000, chr17:47500000-48000000, chr17: 48500000-49000000, chr17: 49000000-49500000,chr17: 49500000-50000000, chr17: 50000000-50500000, chr17:50500000-51000000, chr17: 51000000-51500000, chr17: 53500000-54000000,chr17: 54000000-54500000, chr17: 55000000-55500000, chr17:56500000-57000000, chr17: 57000000-57500000, chr17: 58000000-58500000,chr17: 58500000-59000000, chr17: 59000000-59500000, chr17:59500000-60000000, chr17: 60000000-60500000, chr17: 61500000-62000000,chr17: 62500000-63000000, chr17: 63500000-64000000, chr17:64000000-64500000, chr17: 65000000-65500000, chr17: 66000000-66500000,chr17: 67000000-67500000, chr17: 67500000-68000000, chr17:68000000-68500000, chr17: 73500000-74000000, chr17: 74000000-74500000,chr17: 74500000-75000000, chr17: 75000000-75500000, chr17:75500000-76000000, chr17: 76000000-76500000, chr17: 77000000-77500000,chr17: 78000000-78500000, chr17: 78500000-79000000, chr17:79500000-80000000, chr17: 80000000-80500000, chr17: 82500000-83000000 18chr18: 1000000-1500000, chr18: 3000000-3500000, chr18: 5500000-6000000,chr18: 6500000- 7000000, chr18: 8000000-8500000, chr18: 9000000-9500000,chr18: 10000000-10500000, chr18: 11000000-11500000, chr18:12000000-12500000, chr18: 12500000-13000000, chr18: 14000000-14500000,chr18: 14500000-15000000, chr18: 15000000-15500000, chr18:20500000-21000000, chr18: 21000000-21500000, chr18: 23500000-24000000,chr18: 25000000-25500000, chr18: 27000000-27500000, chr18:27500000-28000000, chr18: 35000000-35500000, chr18: 46000000-46500000,chr18: 47000000-47500000, chr18: 48500000-49000000, chr18:49000000-49500000, chr18: 51000000-51500000, chr18: 53000000-53500000,chr18: 59500000-60000000, chr18: 61000000-61500000, chr18:63000000-63500000, chr18: 64500000-65000000, chr18: 74500000-75000000,chr18: 76000000-76500000, chr18: 78000000-78500000 19 chr19: 0-500000,chr19: 1500000-2000000, chr19: 2000000-2500000, chr19: 2500000-3000000,chr19: 3000000-3500000, chr19: 4000000-4500000, chr19: 4500000-5000000,chr19: 5500000- 6000000, chr19: 6000000-6500000, chr19: 6500000-7000000,chr19: 7000000-7500000, chr19: 7500000-8000000, chr19: 8000000-8500000,chr19: 9500000-10000000, chr19: 10000000- 10500000, chr19:10500000-11000000, chr19: 11000000-11500000, chr19: 11500000-12000000,chr19: 12500000-13000000, chr19: 13000000-13500000, chr19:13500000-14000000, chr19: 14000000-14500000, chr19: 14500000-15000000,chr19: 15500000-16000000, chr19: 16000000-16500000, chr19:16500000-17000000, chr19: 17000000-17500000, chr19: 17500000-18000000,chr19: 18000000-18500000, chr19: 18500000-19000000, chr19:19000000-19500000, chr19: 20500000-21000000, chr19: 22000000-22500000,chr19: 22500000-23000000, chr19: 27500000-28000000, chr19:34000000-34500000, chr19: 35000000-35500000, chr19: 35500000-36000000,chr19: 38000000-38500000, chr19: 38500000-39000000, chr19:39000000-39500000, chr19: 39500000-40000000, chr19: 40000000-40500000,chr19: 40500000-41000000, chr19: 41000000-41500000, chr19:41500000-42000000, chr19: 42000000-42500000, chr19: 43500000-44000000,chr19: 44500000-45000000, chr19: 45000000-45500000, chr19:45500000-46000000, chr19: 46500000-47000000, chr19: 47000000-47500000,chr19: 48000000-48500000, chr19: 48500000-49000000, chr19:49000000-49500000, chr19: 49500000-50000000, chr19: 51000000-51500000,chr19: 51500000-52000000, chr19: 53500000-54000000, chr19:54000000-54500000, chr19: 55000000-55500000, chr19: 58500000-58617616 20chr20: 0-500000, chr20: 1000000-1500000, chr20: 1500000-2000000, chr20:2500000-3000000, chr20: 3500000-4000000, chr20: 4500000-5000000, chr20:5000000-5500000, chr20: 5500000- 6000000, chr20: 8000000-8500000, chr20:12500000-13000000, chr20: 16000000-16500000, chr20: 21000000-21500000,chr20: 21500000-22000000, chr20: 28500000-29000000, chr20:29000000-29500000, chr20: 29500000-30000000, chr20: 30000000-30500000,chr20: 30500000-31000000, chr20: 31500000-32000000, chr20:32000000-32500000, chr20: 33000000-33500000, chr20: 33500000-34000000,chr20: 34000000-34500000, chr20: 36500000-37000000, chr20:37000000-37500000, chr20: 37500000-38000000, chr20: 38000000-38500000,chr20: 39500000-40000000, chr20: 40500000-41000000, chr20:42500000-43000000, chr20: 43500000-44000000, chr20: 44000000-44500000,chr20: 44500000-45000000, chr20: 45000000-45500000, chr20:45500000-46000000, chr20: 46000000-46500000, chr20: 47000000-47500000,chr20: 47500000-48000000, chr20: 48500000-49000000, chr20:49000000-49500000, chr20: 49500000-50000000, chr20: 50000000-50500000,chr20: 50500000-51000000, chr20: 51000000-51500000, chr20:51500000-52000000, chr20: 52000000-52500000, chr20: 52500000-53000000,chr20: 53500000-54000000, chr20: 55000000-55500000, chr20:55500000-56000000, chr20: 59000000-59500000, chr20: 62000000-62500000,chr20: 63000000-63500000 21 chr21: 5000000-5500000, chr21:5500000-6000000, chr21: 6000000-6500000, chr21: 6500000- 7000000, chr21:7000000-7500000, chr21: 7500000-8000000, chr21: 8000000-8500000, chr21:8500000-9000000, chr21: 9000000-9500000, chr21: 9500000-10000000, chr21:10000000- 10500000, chr21: 10500000-11000000, chr21: 13000000-13500000,chr21: 13500000-14000000, chr21: 14000000-14500000, chr21:15500000-16000000, chr21: 16500000-17000000, chr21: 17000000-17500000,chr21: 17500000-18000000, chr21: 23500000-24000000, chr21:25500000-26000000, chr21: 31000000-31500000, chr21: 31500000-32000000,chr21: 33000000-33500000, chr21: 33500000-34000000, chr21:34500000-35000000, chr21: 35000000-35500000, chr21: 36000000-36500000,chr21: 37000000-37500000, chr21: 40000000-40500000, chr21:40500000-41000000, chr21: 42000000-42500000, chr21: 44000000-44500000 22chr22: 10500000-11000000, chr22: 11000000-11500000, chr22:11500000-12000000, chr22: 12000000-12500000, chr22: 12500000-13000000,chr22: 15000000-15500000, chr22: 15500000-16000000, chr22:16000000-16500000, chr22: 16500000-17000000, chr22: 18000000-18500000,chr22: 18500000-19000000, chr22: 20500000-21000000, chr22:21500000-22000000, chr22: 23500000-24000000, chr22: 26000000-26500000,chr22: 27000000-27500000, chr22: 28500000-29000000, chr22:29500000-30000000, chr22: 30000000-30500000, chr22: 31000000-31500000,chr22: 31500000-32000000, chr22: 32500000-33000000, chr22:35000000-35500000, chr22: 35500000-36000000, chr22: 36000000-36500000,chr22: 36500000-37000000, chr22: 37000000-37500000, chr22:37500000-38000000, chr22: 38000000-38500000, chr22: 39000000-39500000,chr22: 40000000-40500000, chr22: 40500000-41000000, chr22:41000000-41500000, chr22: 41500000-42000000, chr22: 48500000-49000000

TABLE 19 1 chr1: 500000-1000000, chr1: 1500000-2000000, chr1:4000000-4500000, chr1: 10000000-10500000, chr1: 16500000-17000000, chr1:18000000-18500000, chr1: 19500000-20000000, chr1: 20000000- 20500000,chr1: 21500000-22000000, chr1: 22500000-23000000, chr1:23000000-23500000, chr1: 25500000-26000000, chr1: 26000000-26500000,chr1: 27000000-27500000, chr1: 27500000- 28000000, chr1:28000000-28500000, chr1: 28500000-29000000, chr1: 29000000-29500000,chr1: 29500000-30000000, chr1: 30500000-31000000, chr1:31500000-32000000, chr1: 32000000- 32500000, chr1: 32500000-33000000,chr1: 33000000-33500000, chr1: 33500000-34000000, chr1:34500000-35000000, chr1: 35500000-36000000, chr1: 36000000-36500000,chr1: 36500000- 37000000, chr1: 37000000-37500000, chr1:38500000-39000000, chr1: 45500000-46000000, chr1: 49500000-50000000,chr1: 50000000-50500000, chr1: 56500000-57000000, chr1: 57000000-57500000, chr1: 58500000-59000000, chr1: 59500000-60000000, chr1:60000000-60500000, chr1: 64000000-64500000, chr1: 74500000-75000000,chr1: 87500000-88000000, chr1: 94500000- 95000000, chr1:97000000-97500000, chr1: 107500000-108000000, chr1: 109500000-110000000,chr1: 110000000-110500000, chr1: 115000000-115500000, chr1:120000000-120500000, chr1: 120500000-121000000, chr1:121000000-121500000, chr1: 125000000-125500000, chr1:143000000-143500000, chr1: 144000000-144500000, chr1:144500000-145000000, chr1: 145000000-145500000, chr1:146000000-146500000, chr1: 146500000-147000000, chr1:148000000-148500000, chr1: 148500000-149000000, chr1:149000000-149500000, chr1: 150000000-150500000, chr1:150500000-151000000, chr1: 151000000-151500000, chr1:151500000-152000000, chr1: 153000000-153500000, chr1:153500000-154000000, chr1: 154500000-155000000, chr1:155500000-156000000, chr1: 156000000-156500000, chr1:156500000-157000000, chr1: 158000000-158500000, chr1:159500000-160000000, chr1: 160000000-160500000, chr1:161000000-161500000, chr1: 162000000-162500000, chr1:175500000-176000000, chr1: 176500000-177000000, chr1:181000000-181500000, chr1: 183000000-183500000, chr1:186000000-186500000, chr1: 190000000-190500000, chr1:192500000-193000000, chr1: 200500000-201000000, chr1:201500000-202000000, chr1: 204000000-204500000, chr1:205000000-205500000, chr1: 208000000-208500000, chr1:209500000-210000000, chr1: 214000000-214500000, chr1:219000000-219500000, chr1: 221000000-221500000, chr1:226000000-226500000, chr1: 229500000-230000000, chr1:230500000-231000000, chr1: 234000000-234500000, chr1:240500000-241000000, chr1: 241500000-242000000, chr1:245000000-245500000, chr1: 247000000-247500000, chr1:248000000-248500000 2 chr2: 3000000-3500000, chr2: 8000000-8500000,chr2: 11500000-12000000, chr2: 22500000- 23000000, chr2:27000000-27500000, chr2: 28500000-29000000, chr2: 36500000-37000000,chr2: 37000000-37500000, chr2: 37500000-38000000, chr2:39000000-39500000, chr2: 44000000- 44500000, chr2: 47000000-47500000,chr2: 48500000-49000000, chr2: 49000000-49500000, chr2:57500000-58000000, chr2: 59500000-60000000, chr2: 61500000-62000000,chr2: 64000000- 64500000, chr2: 64500000-65000000, chr2:65000000-65500000, chr2: 73500000-74000000, chr2: 75000000-75500000,chr2: 87000000-87500000, chr2: 87500000-88000000, chr2: 88500000-89000000, chr2: 89500000-90000000, chr2: 90000000-90500000, chr2:91000000-91500000, chr2: 91500000-92000000, chr2: 92000000-92500000,chr2: 95500000-96000000, chr2: 97000000- 97500000, chr2:102000000-102500000, chr2: 106000000-106500000, chr2: 109500000-110000000, chr2: 110000000-110500000, chr2: 110500000-111000000, chr2:112500000- 113000000, chr2: 113000000-113500000, chr2:118000000-118500000, chr2: 125000000- 125500000, chr2:126500000-127000000, chr2: 127500000-128000000, chr2: 130000000-130500000, chr2: 132000000-132500000, chr2: 132500000-133000000, chr2:134500000- 135000000, chr2: 136000000-136500000, chr2:144500000-145000000, chr2: 145000000- 145500000, chr2:148500000-149000000, chr2: 159000000-159500000, chr2: 162000000-162500000, chr2: 165500000-166000000, chr2: 171500000-172000000, chr2:173500000- 174000000, chr2: 188500000-189000000, chr2:190500000-191000000, chr2: 191000000- 191500000, chr2:197000000-197500000, chr2: 200500000-201000000, chr2: 201500000-202000000, chr2: 206000000-206500000, chr2: 207000000-207500000, chr2:216000000- 216500000, chr2: 218000000-218500000, chr2:219500000-220000000, chr2: 221000000- 221500000, chr2:227500000-228000000, chr2: 229500000-230000000, chr2: 236500000-237000000 3 chr3: 4500000-5000000, chr3: 5000000-5500000, chr3:7000000-7500000, chr3: 9000000-9500000, chr3: 9500000-10000000, chr3:10000000-10500000, chr3: 10500000-11000000, chr3: 12500000- 13000000,chr3: 13500000-14000000, chr3: 21000000-21500000, chr3:21500000-22000000, chr3: 32500000-33000000, chr3: 34000000-34500000,chr3: 36000000-36500000, chr3: 37000000- 37500000, chr3:43500000-44000000, chr3: 44000000-44500000, chr3: 45000000-45500000,chr3: 46000000-46500000, chr3: 47000000-47500000, chr3:48500000-49000000, chr3: 49000000- 49500000, chr3: 49500000-50000000,chr3: 52000000-52500000, chr3: 63500000-64000000, chr3:72000000-72500000, chr3: 75500000-76000000, chr3: 79000000-79500000,chr3: 91000000- 91500000, chr3: 96500000-97000000, chr3:99500000-100000000, chr3: 108500000-109000000, chr3:115000000-115500000, chr3: 127500000-128000000, chr3:128500000-129000000, chr3: 129500000-130000000, chr3:132500000-133000000, chr3: 138500000-139000000, chr3:145500000-146000000, chr3: 149000000-149500000, chr3:152500000-153000000, chr3: 157500000-158000000, chr3:170000000-170500000, chr3: 171500000-172000000, chr3:172000000-172500000, chr3: 184500000-185000000, chr3:185500000-186000000, chr3: 186000000-186500000, chr3:188000000-188500000, chr3: 194500000-195000000, chr3:195000000-195500000, chr3: 196500000-197000000, chr3:198000000-198295559 4 chr4: 2000000-2500000, chr4: 4500000-5000000,chr4: 5500000-6000000, chr4: 7500000-8000000, chr4: 9500000-10000000,chr4: 15000000-15500000, chr4: 16500000-17000000, chr4: 32500000-33000000, chr4: 37500000-38000000, chr4: 40500000-41000000, chr4:49000000-49500000, chr4: 49500000-50000000, chr4: 64000000-64500000,chr4: 67500000-68000000, chr4: 70500000- 71000000, chr4:73500000-74000000, chr4: 78000000-78500000, chr4: 80000000-80500000,chr4: 88500000-89000000, chr4: 103000000-103500000, chr4:112500000-113000000, chr4: 125500000-126000000, chr4:145000000-145500000, chr4: 146000000-146500000, chr4:152000000-152500000, chr4: 161500000-162000000, chr4:164000000-164500000, chr4: 175500000-176000000, chr4:176000000-176500000, chr4: 184500000-185000000, chr4:185500000-186000000, chr4: 186000000-186500000, chr4:187000000-187500000, chr4: 190000000-190214555 5 chr5:10500000-11000000, chr5: 11000000-11500000, chr5: 11500000-12000000,chr5: 13500000- 14000000, chr5: 21000000-21500000, chr5:31500000-32000000, chr5: 34000000-34500000, chr5: 38000000-38500000,chr5: 43500000-44000000, chr5: 54000000-54500000, chr5: 56000000-56500000, chr5: 61000000-61500000, chr5: 69500000-70000000, chr5:70000000-70500000, chr5: 70500000-71000000, chr5: 71000000-71500000,chr5: 80000000-80500000, chr5: 81500000- 82000000, chr5:91000000-91500000, chr5: 94000000-94500000, chr5: 112500000-113000000,chr5: 119500000-120000000, chr5: 124000000-124500000, chr5:138000000-138500000, chr5: 139500000-140000000, chr5:140500000-141000000, chr5: 148000000-148500000, chr5:148500000-149000000, chr5: 157500000-158000000, chr5:158000000-158500000, chr5: 158500000-159000000, chr5:171500000-172000000, chr5: 172000000-172500000, chr5:172500000-173000000, chr5: 173500000-174000000, chr5:174500000-175000000, chr5: 176000000-176500000, chr5:176500000-177000000 6 chr6: 2500000-3000000, chr6: 6500000-7000000,chr6: 13000000-13500000, chr6: 15000000- 15500000, chr6:17500000-18000000, chr6: 25000000-25500000, chr6: 26000000-26500000,chr6: 26500000-27000000, chr6: 33000000-33500000, chr6:33500000-34000000, chr6: 36000000- 36500000, chr6: 36500000-37000000,chr6: 37000000-37500000, chr6: 40000000-40500000, chr6:41000000-41500000, chr6: 41500000-42000000, chr6: 42000000-42500000,chr6: 42500000- 43000000, chr6: 43000000-43500000, chr6:43500000-44000000, chr6: 57500000-58000000, chr6: 58000000-58500000,chr6: 60000000-60500000, chr6: 60500000-61000000, chr6: 77500000-78000000, chr6: 79500000-80000000, chr6: 81000000-81500000, chr6:86000000-86500000, chr6: 88500000-89000000, chr6: 107000000-107500000,chr6: 109000000-109500000, chr6: 112000000-112500000, chr6:114000000-114500000, chr6: 119500000-120000000, chr6:121000000-121500000, chr6: 124000000-124500000, chr6:129000000-129500000, chr6: 130500000-131000000, chr6:154000000-154500000, chr6: 160000000-160500000, chr6:163500000-164000000, chr6: 168500000-169000000, chr6:170000000-170500000, chr6: 170500000-170805979 7 chr7: 5500000-6000000,chr7: 6000000-6500000, chr7: 25500000-26000000, chr7: 26000000-26500000, chr7: 26500000-27000000, chr7: 30500000-31000000, chr7:32500000-33000000, chr7: 36000000-36500000, chr7: 36500000-37000000,chr7: 39500000-40000000, chr7: 41500000- 42000000, chr7:44000000-44500000, chr7: 44500000-45000000, chr7: 54000000-54500000,chr7: 55500000-56000000, chr7: 56500000-57000000, chr7:57500000-58000000, chr7: 58000000- 58500000, chr7: 63000000-63500000,chr7: 63500000-64000000, chr7: 64000000-64500000, chr7:65000000-65500000, chr7: 65500000-66000000, chr7: 66000000-66500000,chr7: 66500000- 67000000, chr7: 73500000-74000000, chr7:74000000-74500000, chr7: 74500000-75000000, chr7: 75500000-76000000,chr7: 76000000-76500000, chr7: 76500000-77000000, chr7: 95500000-96000000, chr7: 97500000-98000000, chr7: 100000000-100500000, chr7:100500000-101000000, chr7: 101500000-102000000, chr7:105000000-105500000, chr7: 108000000-108500000, chr7:112000000-112500000, chr7: 125000000-125500000, chr7:127500000-128000000, chr7: 128000000-128500000, chr7:128500000-129000000, chr7: 131500000-132000000, chr7:133000000-133500000, chr7: 143000000-143500000, chr7:145000000-145500000 8 chr8: 0-500000, chr8: 8000000-8500000, chr8:8500000-9000000, chr8: 12000000-12500000, chr8: 15000000-15500000, chr8:17500000-18000000, chr8: 20000000-20500000, chr8: 20500000- 21000000,chr8: 22500000-23000000, chr8: 27000000-27500000, chr8:29500000-30000000, chr8: 37500000-38000000, chr8: 38000000-38500000,chr8: 41500000-42000000, chr8: 42000000- 42500000, chr8:42500000-43000000, chr8: 46000000-46500000, chr8: 48000000-48500000,chr8: 57000000-57500000, chr8: 57500000-58000000, chr8:58500000-59000000, chr8: 60500000- 61000000, chr8: 72000000-72500000,chr8: 73500000-74000000, chr8: 85500000-86000000, chr8:91500000-92000000, chr8: 94500000-95000000, chr8: 96000000-96500000,chr8: 97000000- 97500000, chr8: 98000000-98500000, chr8:101000000-101500000, chr8: 113000000-113500000, chr8:114500000-115000000, chr8: 117500000-118000000, chr8:122500000-123000000, chr8: 125000000-125500000, chr8:126000000-126500000, chr8: 128500000-129000000, chr8:129000000-129500000, chr8: 130000000-130500000, chr8:132000000-132500000, chr8: 133500000-134000000, chr8:138500000-139000000, chr8: 144000000-144500000 9 chr9: 5500000-6000000,chr9: 10000000-10500000, chr9: 21000000-21500000, chr9: 21500000-22000000, chr9: 29000000-29500000, chr9: 33000000-33500000, chr9:34000000-34500000, chr9: 34500000-35000000, chr9: 35500000-36000000,chr9: 36000000-36500000, chr9: 39000000- 39500000, chr9:39500000-40000000, chr9: 40000000-40500000, chr9: 40500000-41000000,chr9: 41000000-41500000, chr9: 41500000-42000000, chr9:42000000-42500000, chr9: 42500000- 43000000, chr9: 60500000-61000000,chr9: 61500000-62000000, chr9: 62000000-62500000, chr9:62500000-63000000, chr9: 63000000-63500000, chr9: 63500000-64000000,chr9: 64000000- 64500000, chr9: 64500000-65000000, chr9:65000000-65500000, chr9: 65500000-66000000, chr9: 66000000-66500000,chr9: 66500000-67000000, chr9: 67000000-67500000, chr9: 67500000-68000000, chr9: 71500000-72000000, chr9: 72500000-73000000, chr9:74500000-75000000, chr9: 77500000-78000000, chr9: 80500000-81000000,chr9: 84000000-84500000, chr9: 86000000- 86500000, chr9:89500000-90000000, chr9: 92500000-93000000, chr9: 105000000-105500000,chr9: 114000000-114500000, chr9: 114500000-115000000, chr9:116000000-116500000, chr9: 120500000-121000000, chr9:121500000-122000000, chr9: 122000000-122500000, chr9:123000000-123500000, chr9: 127500000-128000000, chr9:129000000-129500000, chr9: 129500000-130000000, chr9:131500000-132000000, chr9: 132000000-132500000 10 chr10:3500000-4000000, chr10: 6000000-6500000, chr10: 9000000-9500000, chr10:21000000- 21500000, chr10: 22500000-23000000, chr10: 23500000-24000000,chr10: 38000000-38500000, chr10: 38500000-39000000, chr10:42000000-42500000, chr10: 46000000-46500000, chr10: 46500000-47000000,chr10: 47500000-48000000, chr10: 50000000-50500000, chr10:69000000-69500000, chr10: 71500000-72000000, chr10: 72000000-72500000,chr10: 77500000-78000000, chr10: 94000000-94500000, chr10:94500000-95000000, chr10: 95000000-95500000, chr10: 97000000-97500000,chr10: 97500000-98000000, chr10: 98000000-98500000, chr10:98500000-99000000, chr10: 100500000-101000000, chr10:101000000-101500000, chr10: 104000000-104500000, chr10:109500000-110000000, chr10: 110000000-110500000, chr10:111500000-112000000, chr10: 116000000-116500000, chr10:123500000-124000000, chr10: 133500000-133797422 11 chr11: 0-500000,chr11: 1500000-2000000, chr11: 3500000-4000000, chr11: 4000000-4500000,chr11: 5500000-6000000, chr11: 8500000-9000000, chr11: 9500000-10000000,chr11: 12000000- 12500000, chr11: 15500000-16000000, chr11:17500000-18000000, chr11: 28000000-28500000, chr11: 32000000-32500000,chr11: 44500000-45000000, chr11: 46000000-46500000, chr11:47000000-47500000, chr11: 49000000-49500000, chr11: 49500000-50000000,chr11: 56500000-57000000, chr11: 57500000-58000000, chr11:59500000-60000000, chr11: 62000000-62500000, chr11: 62500000-63000000,chr11: 64500000-65000000, chr11: 65500000-66000000, chr11:66000000-66500000, chr11: 69500000-70000000, chr11: 72000000-72500000,chr11: 72500000-73000000, chr11: 73000000-73500000, chr11:73500000-74000000, chr11: 78000000-78500000, chr11: 79000000-79500000,chr11: 81500000-82000000, chr11: 86000000-86500000, chr11:89000000-89500000, chr11: 89500000-90000000, chr11: 99000000-99500000,chr11: 111000000-111500000, chr11: 111500000-112000000, chr11:113500000-114000000, chr11: 117000000-117500000, chr11:119000000-119500000, chr11: 120500000-121000000, chr11:121000000-121500000, chr11: 122500000-123000000, chr11:123500000-124000000, chr11: 126000000-126500000, chr11:126500000-127000000, chr11: 134500000-135000000 12 chr12: 0-500000,chr12: 500000-1000000, chr12: 3500000-4000000, chr12: 6000000-6500000,chr12: 9000000-9500000, chr12: 12500000-13000000, chr12:17500000-18000000, chr12: 28000000-28500000, chr12: 37000000-37500000,chr12: 37500000-38000000, chr12: 38000000-38500000, chr12:39500000-40000000, chr12: 42000000-42500000, chr12: 47500000-48000000,chr12: 49000000-49500000, chr12: 52500000-53000000, chr12:53000000-53500000, chr12: 53500000-54000000, chr12: 54000000-54500000,chr12: 55500000-56000000, chr12: 56000000-56500000, chr12:57000000-57500000, chr12: 61000000-61500000, chr12: 66500000-67000000,chr12: 69500000-70000000, chr12: 74500000-75000000, chr12:76000000-76500000, chr12: 79500000-80000000, chr12: 80000000-80500000,chr12: 93000000-93500000, chr12: 93500000-94000000, chr12:95500000-96000000, chr12: 105000000-105500000, chr12:106500000-107000000, chr12: 109500000-110000000, chr12:110500000-111000000, chr12: 111000000-111500000, chr12:111500000-112000000, chr12: 112000000-112500000, chr12:112500000-113000000, chr12: 113000000-113500000, chr12:113500000-114000000, chr12: 116500000-117000000, chr12:120000000-120500000, chr12: 120500000-121000000, chr12:121000000-121500000, chr12: 121500000-122000000, chr12:122000000-122500000, chr12: 123500000-124000000, chr12:128500000-129000000, chr12: 129500000-130000000 13 chr13:18000000-18500000, chr13: 18500000-19000000, chr13: 21000000-21500000,chr13: 29000000-29500000, chr13: 39000000-39500000, chr13:41000000-41500000, chr13: 47500000-48000000, chr13: 49500000-50000000,chr13: 51000000-51500000, chr13: 57000000-57500000, chr13:60500000-61000000, chr13: 67500000-68000000, chr13: 75500000-76000000,chr13: 85000000-85500000, chr13: 85500000-86000000, chr13:86500000-87000000, chr13: 92500000-93000000, chr13: 101500000-102000000,chr13: 113500000-114000000 14 chr14: 18000000-18500000, chr14:18500000-19000000, chr14: 19000000-19500000, chr14: 20000000-20500000,chr14: 21000000-21500000, chr14: 22500000-23000000, chr14:23000000-23500000, chr14: 28000000-28500000, chr14: 30000000-30500000,chr14: 32500000-33000000, chr14: 35000000-35500000, chr14:37000000-37500000, chr14: 39000000-39500000, chr14: 44500000-45000000,chr14: 55000000-55500000, chr14: 55500000-56000000, chr14:60000000-60500000, chr14: 67000000-67500000, chr14: 68500000-69000000,chr14: 73000000-73500000, chr14: 75000000-75500000, chr14:76000000-76500000, chr14: 77000000-77500000, chr14: 81000000-81500000,chr14: 88500000-89000000, chr14: 90500000-91000000, chr14:92000000-92500000, chr14: 92500000-93000000, chr14: 94500000-95000000,chr14: 95500000-96000000, chr14: 96000000-96500000, chr14:96500000-97000000, chr14: 97000000-97500000, chr14: 97500000-98000000,chr14: 99500000-100000000, chr14: 103000000-103500000, chr14:104000000-104500000 15 chr15: 17000000-17500000, chr15:19500000-20000000, chr15: 20000000-20500000, chr15: 20500000-21000000,chr15: 21000000-21500000, chr15: 21500000-22000000, chr15:23000000-23500000, chr15: 30000000-30500000, chr15: 30500000-31000000,chr15: 31500000-32000000, chr15: 34000000-34500000, chr15:38000000-38500000, chr15: 39500000-40000000, chr15: 41000000-41500000,chr15: 46000000-46500000, chr15: 57500000-58000000, chr15:60000000-60500000, chr15: 63000000-63500000, chr15: 63500000-64000000,chr15: 64500000-65000000, chr15: 65000000-65500000, chr15:66500000-67000000, chr15: 69000000-69500000, chr15: 70000000-70500000,chr15: 74500000-75000000, chr15: 79500000-80000000, chr15:81000000-81500000, chr15: 81500000-82000000, chr15: 84000000-84500000,chr15: 86500000-87000000, chr15: 90000000-90500000, chr15:91500000-92000000, chr15: 94000000-94500000 16 chr16: 6500000-7000000,chr16: 10500000-11000000, chr16: 11500000-12000000, chr16:13000000-13500000, chr16: 13500000-14000000, chr16: 14000000-14500000,chr16: 14500000-15000000, chr16: 15000000-15500000, chr16:16000000-16500000, chr16: 17500000-18000000, chr16: 18000000-18500000,chr16: 21500000-22000000, chr16: 23500000-24000000, chr16:24500000-25000000, chr16: 26000000-26500000, chr16: 26500000-27000000,chr16: 27000000-27500000, chr16: 27500000-28000000, chr16:29000000-29500000, chr16: 30500000-31000000, chr16: 31000000-31500000,chr16: 32000000-32500000, chr16: 32500000-33000000, chr16:33000000-33500000, chr16: 33500000-34000000, chr16: 34000000-34500000,chr16: 34500000-35000000, chr16: 46000000-46500000, chr16:49000000-49500000, chr16: 49500000-50000000, chr16: 53000000-53500000,chr16: 59500000-60000000, chr16: 66500000-67000000, chr16:67500000-68000000, chr16: 71500000-72000000, chr16: 72000000-72500000,chr16: 74000000-74500000, chr16: 76000000-76500000, chr16:79500000-80000000, chr16: 82500000-83000000, chr16: 84500000-85000000,chr16: 85500000-86000000, chr16: 90000000-90338345 17 chr17:500000-1000000, chr17: 1000000-1500000, chr17: 1500000-2000000, chr17:2500000- 3000000, chr17: 4000000-4500000, chr17: 4500000-5000000, chr17:5000000-5500000, chr17: 7000000-7500000, chr17: 7500000-8000000, chr17:8000000-8500000, chr17: 8500000- 9000000, chr17: 10000000-10500000,chr17: 10500000-11000000, chr17: 13000000-13500000, chr17:19500000-20000000, chr17: 21500000-22000000, chr17: 26500000-27000000,chr17: 27500000-28000000, chr17: 28500000-29000000, chr17:31000000-31500000, chr17: 33000000-33500000, chr17: 33500000-34000000,chr17: 36500000-37000000, chr17: 38500000-39000000, chr17:40000000-40500000, chr17: 41500000-42000000, chr17: 42500000-43000000,chr17: 43500000-44000000, chr17: 44000000-44500000, chr17:45000000-45500000, chr17: 48500000-49000000, chr17: 49500000-50000000,chr17: 56000000-56500000, chr17: 56500000-57000000, chr17:59000000-59500000, chr17: 59500000-60000000, chr17: 64000000-64500000,chr17: 65000000-65500000, chr17: 65500000-66000000, chr17:66000000-66500000, chr17: 67000000-67500000, chr17: 70500000-71000000,chr17: 71000000-71500000, chr17: 72500000-73000000, chr17:74000000-74500000, chr17: 75000000-75500000, chr17: 80000000-80500000 18chr18: 2500000-3000000, chr18: 3500000-4000000, chr18: 9500000-10000000,chr18: 14000000- 14500000, chr18: 15000000-15500000, chr18:20500000-21000000, chr18: 24000000-24500000, chr18: 42500000-43000000,chr18: 50500000-51000000, chr18: 53500000-54000000, chr18:67000000-67500000, chr18: 73500000-74000000 19 chr19: 0-500000, chr19:500000-1000000, chr19: 1000000-1500000, chr19: 1500000-2000000, chr19:2500000-3000000, chr19: 3000000-3500000, chr19: 4500000-5000000, chr19:5500000- 6000000, chr19: 6000000-6500000, chr19: 6500000-7000000, chr19:7500000-8000000, chr19: 8000000-8500000, chr19: 8500000-9000000, chr19:9500000-10000000, chr19: 10000000- 10500000, chr19: 10500000-11000000,chr19: 11000000-11500000, chr19: 12500000-13000000, chr19:14500000-15000000, chr19: 15500000-16000000, chr19: 16000000-16500000,chr19: 16500000-17000000, chr19: 17000000-17500000, chr19:17500000-18000000, chr19: 18000000-18500000, chr19: 19000000-19500000,chr19: 27500000-28000000, chr19: 35000000-35500000, chr19:35500000-36000000, chr19: 38000000-38500000, chr19: 38500000-39000000,chr19: 39000000-39500000, chr19: 39500000-40000000, chr19:40000000-40500000, chr19: 40500000-41000000, chr19: 41000000-41500000,chr19: 41500000-42000000, chr19: 42000000-42500000, chr19:43000000-43500000, chr19: 44500000-45000000, chr19: 45000000-45500000,chr19: 45500000-46000000, chr19: 46500000-47000000, chr19:47000000-47500000, chr19: 48000000-48500000, chr19: 49500000-50000000,chr19: 50500000-51000000, chr19: 51000000-51500000, chr19:52000000-52500000, chr19: 55500000-56000000, chr19: 56000000-56500000 20chr20: 1500000-2000000, chr20: 2000000-2500000, chr20: 3000000-3500000,chr20: 5000000- 5500000, chr20: 5500000-6000000, chr20:10000000-10500000, chr20: 10500000-11000000, chr20: 14500000-15000000,chr20: 20500000-21000000, chr20: 25000000-25500000, chr20:25500000-26000000, chr20: 26000000-26500000, chr20: 28500000-29000000,chr20: 29000000-29500000, chr20: 29500000-30000000, chr20:30000000-30500000, chr20: 30500000-31000000, chr20: 31500000-32000000,chr20: 32000000-32500000, chr20: 33000000-33500000, chr20:35000000-35500000, chr20: 35500000-36000000, chr20: 36500000-37000000,chr20: 37000000-37500000, chr20: 38500000-39000000, chr20:40500000-41000000, chr20: 44000000-44500000, chr20: 44500000-45000000,chr20: 46000000-46500000, chr20: 47000000-47500000, chr20:48000000-48500000, chr20: 48500000-49000000, chr20: 50000000-50500000,chr20: 51500000-52000000, chr20: 53500000-54000000, chr20:56500000-57000000, chr20: 57000000-57500000, chr20: 57500000-58000000,chr20: 58500000-59000000, chr20: 61000000-61500000, chr20:62500000-63000000 21 chr21: 5000000-5500000, chr21: 5500000-6000000,chr21: 6000000-6500000, chr21: 6500000- 7000000, chr21: 7000000-7500000,chr21: 7500000-8000000, chr21: 8000000-8500000, chr21: 8500000-9000000,chr21: 9000000-9500000, chr21: 9500000-10000000, chr21: 10000000-10500000, chr21: 13000000-13500000, chr21: 13500000-14000000, chr21:14500000-15000000, chr21: 15000000-15500000, chr21: 18000000-18500000,chr21: 24500000-25000000, chr21: 29000000-29500000, chr21:31000000-31500000, chr21: 32500000-33000000, chr21: 33500000-34000000,chr21: 35500000-36000000, chr21: 36000000-36500000, chr21:38000000-38500000, chr21: 39500000-40000000 22 chr22: 10500000-11000000,chr22: 11000000-11500000, chr22: 11500000-12000000, chr22:12000000-12500000, chr22: 12500000-13000000, chr22: 15000000-15500000,chr22: 15500000-16000000, chr22: 16000000-16500000, chr22:18500000-19000000, chr22: 19000000-19500000, chr22: 23500000-24000000,chr22: 25000000-25500000, chr22: 27000000-27500000, chr22:27500000-28000000, chr22: 29500000-30000000, chr22: 31500000-32000000,chr22: 32000000-32500000, chr22: 35000000-35500000, chr22:35500000-36000000, chr22: 36500000-37000000, chr22: 37500000-38000000,chr22: 38000000-38500000, chr22: 38500000-39000000, chr22:41500000-42000000, chr22: 42500000-43000000, chr22: 43000000-43500000,chr22: 48000000-48500000

TABLE 20 1 1_10000000_10500000, 1_101000000_101500000,1_103000000_103500000, 1_104500000_105000000, 1_107500000_108000000,1_108500000_109000000, 1_109000000_109500000, 1_109500000_110000000,1_110000000_110500000, 1_110500000_111000000, 1_111500000_112000000,1_112500000_113000000, 1_114000000_114500000, 1_11500000_12000000,1_115000000_115500000, 1_116000000_116500000, 1_116500000_117000000,1_118500000_119000000, 1_12000000_12500000, 1_120000000_120500000,1_120500000_121000000, 1_121000000_121500000, 1_12500000_13000000,1_125000000_125500000, 1_13000000_13500000, 1_143000000_143500000,1_143500000_144000000, 1_144000000_144500000, 1_144500000_145000000,1_145000000_145500000, 1_146000000_146500000, 1_146500000_147000000,1_147500000_148000000, 1_148000000_148500000, 1_148500000_149000000,1_149000000_149500000, 1_149500000_150000000, 1_1500000_2000000,1_150000000_150500000, 1_150500000_151000000, 1_151000000_151500000,1_151500000_152000000, 1_152000000_152500000, 1_153000000_153500000,1_153500000_154000000, 1_154000000_154500000, 1_154500000_155000000,1_15500000_16000000, 1_155000000_155500000, 1_155500000_156000000,1_156000000_156500000, 1_156500000_157000000, 1_157000000_157500000,1_158000000_158500000, 1_158500000_159000000, 1_159000000_159500000,1_159500000_160000000, 1_16000000_16500000, 1_160000000_160500000,1_160500000_161000000, 1_161000000_161500000, 1_161500000_162000000,1_162000000_162500000, 1_163500000_164000000, 1_16500000_17000000,1_165500000_166000000, 1_167000000_167500000, 1_167500000_168000000,1_168500000_169000000, 1_169500000_170000000, 1_171000000_171500000,1_171500000_172000000, 1_172500000_173000000, 1_173500000_174000000,1_174000000_174500000, 1_175000000_175500000, 1_175500000_176000000,1_176500000_177000000, 1_177500000_178000000, 1_179000000_179500000,1_18000000_18500000, 1_181000000_181500000, 1_182000000_182500000,1_182500000_183000000, 1_183000000_183500000, 1_183500000_184000000,1_184500000_185000000, 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17_79500000_80000000,17_8000000_8500000, 17_80000000_80500000, 17_82500000_83000000,17_8500000_9000000, 18 18_1000000_1500000, 18_10000000_10500000,18_11000000_11500000, 18_12000000_12500000, 18_12500000_13000000,18_14000000_14500000, 18_14500000_15000000, 18_15000000_15500000,18_20500000_21000000, 18_21000000_21500000, 18_23500000_24000000,18_24000000_24500000, 18_2500000_3000000, 18_25000000_25500000,18_27000000_27500000, 18_27500000_28000000, 18_3000000_3500000,18_30500000_31000000, 18_31500000_32000000, 18_3500000_4000000,18_35000000_35500000, 18_39000000_39500000, 18_42000000_42500000,18_42500000_43000000, 18_46000000_46500000, 18_47000000_47500000,18_48500000_49000000, 18_49000000_49500000, 18_5000000_5500000,18_50500000_51000000, 18_51000000_51500000, 18_53000000_53500000,18_53500000_54000000, 18_5500000_6000000, 18_59500000_60000000,18_61000000_61500000, 18_63000000_63500000, 18_64500000_65000000,18_6500000_7000000, 18_65000000_65500000, 18_67000000_67500000,18_7000000_7500000, 18_73000000_73500000, 18_73500000_74000000,18_74500000_75000000, 18_76000000_76500000, 18_78000000_78500000,18_8000000_8500000, 18_9000000_9500000, 18_9500000_10000000 1919_0_500000, 19_1000000_1500000, 19_10000000_10500000,19_10500000_11000000, 19_11000000_11500000, 19_11500000_12000000,19_12500000_13000000, 19_13000000_13500000, 19_13500000_14000000,19_14000000_14500000, 19_14500000_15000000, 19_1500000_2000000,19_15000000_15500000, 19_15500000_16000000, 19_16000000_16500000,19_16500000_17000000, 19_17000000_17500000, 19_17500000_18000000,19_18000000_18500000, 19_18500000_19000000, 19_19000000_19500000,19_2000000_2500000, 19_20500000_21000000, 19_21000000_21500000,19_21500000_22000000, 19_22000000_22500000, 19_22500000_23000000,19_2500000_3000000, 19_27500000_28000000, 19_28000000_28500000,19_3000000_3500000, 19_34000000_34500000, 19_35000000_35500000,19_35500000_36000000, 19_38000000_38500000, 19_38500000_39000000,19_39000000_39500000, 19_39500000_40000000, 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20_49000000_49500000,20_49500000_50000000, 20_5000000_5500000, 20_50000000_50500000,20_50500000_51000000, 20_51000000_51500000, 20_51500000_52000000,20_52000000_52500000, 20_52500000_53000000, 20_53500000_54000000,20_5500000_6000000, 20_55000000_55500000, 20_55500000_56000000,20_56500000_57000000, 20_57000000_57500000, 20_57500000_58000000,20_58500000_59000000, 20_59000000_59500000, 20_61000000_61500000,20_62000000_62500000, 20_62500000_63000000, 20_63000000_63500000,20_8000000_8500000 21 21_10000000_10500000, 21_10500000_11000000,21_13000000_13500000, 21_13500000_14000000, 21_14000000_14500000,21_14500000_15000000, 21_15000000_15500000, 21_15500000_16000000,21_16500000_17000000, 21_17000000_17500000, 21_17500000_18000000,21_18000000_18500000, 21_23500000_24000000, 21_24500000_25000000,21_25500000_26000000, 21_29000000_29500000, 21_31000000_31500000,21_31500000_32000000, 21_32500000_33000000, 21_33000000_33500000,21_33500000_34000000, 21_34500000_35000000, 21_35000000_35500000,21_35500000_36000000, 21_36000000_36500000, 21_37000000_37500000,21_38000000_38500000, 21_39500000_40000000, 21_40000000_40500000,21_40500000_41000000, 21_42000000_42500000, 21_44000000_44500000,21_44500000_45000000, 21_5000000_5500000, 21_5500000_6000000,21_6000000_6500000, 21_6500000_7000000, 21_7000000_7500000,21_7500000_8000000, 21_8000000_8500000, 21_8500000_9000000,21_9000000_9500000, 21_9500000_10000000, 22 22_10500000_11000000,22_11000000_11500000, 22_11500000_12000000, 22_12000000_12500000,22_12500000_13000000, 22_15000000_15500000, 22_15500000_16000000,22_16000000_16500000, 22_16500000_17000000, 22_18000000_18500000,22_18500000_19000000, 22_19000000_19500000, 22_20500000_21000000,22_21000000_21500000, 22_21500000_22000000, 22_23000000_23500000,22_23500000_24000000, 22_25000000_25500000, 22_26000000_26500000,22_27000000_27500000, 22_27500000_28000000, 22_28500000_29000000,22_29500000_30000000, 22_30000000_30500000, 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Example 16. Characterization of the rbcDNA Signature in Healthy Donorsand Cancer Patients

Genome-wide sequencing profiles revealed rbcDNA signals distributeacross autosomal chromosomes with specific patterns distinct from thoseof the corresponding genomic DNA (gDNA) (FIG. 15A). The mean genomiccoverage of rbcDNA is higher in healthy donors compared to that ofcancer patients, while no significant difference in coverage is observedamong patients of different cancer types (FIGS. 15B and 15C).Nonetheless, genome-wide analysis showed pronounced signal enrichment ofintergenic, intronic and exonic regions in rbcDNA of cancer patientsversus healthy donors. A modest differential enrichment of rbcDNAsignals was detected in intergenic and intronic regions of CRC patientscompared to patients of other cancer types (FIG. 15D).

It can be clearly seen from the above examples that the inventors havesuccessfully isolated the micronuclei DNA of peripheral red blood cells,and constructed a classifier for cancer detection by using themicronuclei DNA of peripheral red blood cells, thus realizing theeffective detection of cancer, which is of great significance forclinical screening, diagnosis, classification and staging of cancer.

Although the specific embodiments of the present invention have beendescribed in detail, it will be understood by those skilled in the artthat various modifications and variations can be made to the details inlight of all the teachings disclosed, and these changes are within thescope of protection of the present invention. The full scope of theinvention is provided by the appended claims and any equivalentsthereof.

1.-38. (canceled)
 39. A method of treating a cancer in a subject in needthereof, the method comprising: a) obtaining a peripheral blood samplefrom the subject; b) isolating red blood cells from the peripheral bloodsample; c) extracting micronuclei DNA from the isolated red blood cells;d) detecting presence and/or levels of a gene classifier in themicronuclei DNA; e) comparing the detected gene classifier or levelsthereof in the sample with a control to thereby diagnose or detect thecancer in the subject; and f) treating the subject determined to have ordiagnosed with cancer with an anti-cancer agent.
 40. The methodaccording to claim 39, wherein step (b) comprises (i) subjecting theperipheral blood sample to density gradient centrifugation to obtain amononuclear cell layer and a red blood cell layer, (ii) collecting thered blood cells from the bottom of the red blood cell layer, and (iii)filtrating the collected red blood cells two or more times through 10 μmcell strainers.
 41. The method according to claim 39, wherein step (c)comprises (i) treating the isolated red blood cells with a red bloodcell lysis buffer, (ii) treating the lysed red blood cells with anextraction buffer comprising proteinase K, and (iii) extracting themicronuclei DNA from the extraction buffer.
 42. The method of claim 41,further comprising sequencing the micronuclei DNA to thereby detect thepresence and/or levels of a gene classifier.
 43. The method according toclaim 42, further comprising amplifying the micronuclei DNA prior toperforming the sequencing, wherein the amplifying uses a method selectedfrom the group consisting of multiple displacement amplification (MDA),Multiple Annealing and Looping-based Amplification Cycles (MALBAC) anddegenerate oligonucleotide primer PCR (DOP-PCR).
 44. The methodaccording to claim 42, wherein the sequencing is high-throughputsequencing.
 45. The method according to claim 39, further comprisingbefore step f), removing sequence reads that are more enriched byperipheral blood mononuclear cells relative to erythrocyte micronucleiDNA.
 46. The method according to claim 39, wherein the gene classifiercomprises the genes shown in Tables 2, 4, 6, 8 and
 10. 47. The methodaccording to claim 39, wherein the cancer is selected from the groupconsisting of lung cancer, cervical cancer, hepatocellular carcinoma,and colorectal cancer.
 48. The method according to claim 39, furthercomprising determining type and/or stage of cancer by analyzing the geneclassifier.
 49. A method for constructing a system for early detectionor diagnosis of cancer, the method comprising: a) obtaining a peripheralblood sample from healthy subjects and subjects diagnosed with cancer;b) isolating red blood cells from the peripheral blood sample from eachsubject; c) extracting micronuclei DNA from the isolated red bloodcells; d) performing sequencing on the micronuclei DNA to obtainfragment sequence information of the micronuclei DNA; e) comparing thefragment sequence information of micronuclei DNA from peripheral redblood cells in healthy subjects and subjects diagnosed with cancer; f)classifying the signature DNA fragment set for a specific canceraccording to the differences in the distribution of the fragment inhealthy subjects and subjects diagnosed with cancer; g) obtaining a geneclassifier for cancer detection or diagnosis, wherein the geneclassifier is used in the system for early detection or diagnosis ofcancer.
 50. The method according to claim 49, further comprising beforestep e), obtaining an enriched fragment in a specific chromosome regionof the peripheral red blood cell micronuclei DNA of the subject relativeto sequenced reads of the peripheral blood mononuclear cell genome DNAof the subject, thereby obtaining specific cleavage fragments of theperipheral red blood cell of the subject.
 51. The method according toclaim 49, wherein in step f) the characteristic DNA fragment set for aspecific cancer is classified through hierarchical cluster analysis. 52.The method according to claim 49, wherein the cancer is selected fromthe group consisting of lung cancer, cervical cancer, hepatocellularcarcinoma, and colorectal cancer.
 53. The method according claim 49,wherein the fragment sequence information of micronuclei DNA are furtherclassified for type or stage of cancer.
 54. A kit for early detection ordiagnosis of cancer, the kit comprising: a) reagents for detectingexpression of a gene classifier comprising the genes shown in Tables 2,4, 6, 8 and 10; and b) instructions for use.
 55. The kit of claim 54,wherein the cancer is selected from the group consisting of lung cancer,cervical cancer, hepatocellular carcinoma, and colorectal cancer.